the role of fructose in pancreatic cancer cells docx
TRANSCRIPT
SEMINAR REPORT
On
THE ROLE OF FRUCTOSE IN PANCREATIC CANCER CELLS
Submitted by
ADJEKUKOR, UFUOMA CYNTHIA
13CP015803
BIOCHEMISTRY PROGRAMME
To the
DEPARTMENT OF BIOLOGICAL SCIENCES
COLLEGE OF SCIENCE AND TECHNOLOGY
COVENANT UNIVERSITY
IN FULFILLMENT OF THE REQUIREMENT FOR THE SEMINAR COURSE
(BCH 418)
Supervised by
DR T.M. DOKUNMU
Signature
SEPTEMBER 2016
i
CERTIFICATION
This is to certify that Adjekukor, Ufuoma Cynthia with matriculation number 13CP015803, of the
Department of Biological Sciences, College of Science and Technology, Covenant University did this
seminar report titled ‘The Role of Fructose in Pancreatic Cancer Cells’, under the supervision of Dr
T.M. Dokunmu.
DR T.M. DOKUNMU DR T.M. DOKUNMU
(SUPERVISOR) (SEMINAR COORDINATOR)
DR E.O. OMOTOSHO PROF A.A. AJAYI
(PROGRAMME COORDINATOR) (HOD, BIOLOGICAL SCIENCE)
ii
DEDICATION
I dedicate this work to God Almighty, my parents, Mr & Mrs I.O. Adjekukor, my brothers: Davis,
Christian and Cyril for their unending love and support throughout the preparation of this seminar report.
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ACKNOWLEDGEMENTS
I acknowledge God Almighty, my parents Mr and Mrs Adjekukor, my siblings, and my ever-able
supervisor Dr T.M. Dokunmu for her time and commitment. I also acknowledge the head of the
department Prof A.A. AJAYI, biochemistry programme coordinator Dr E.O. Omotosho and biochemistry
seminar coordinator Dr T.M. Dokunmu.
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CONTENTS
TITLE PAGE………………………………………………………………….........................i
CERTIFICATION………………………………………………............................................ii
DEDICATION……………………………………………………………………………....iii
ACKNOWLEDGEMENT……………………………………………...................................iv
CONTENTS……………………………………………….....................................................v
LIST OF TABLES AND FIGURES………………………………………………...……..viii
SUMMARY……………………………………………….....................................................ix
CHAPTER ONE
1.0 Introduction.………………………………………………. ……………………….…...01
1.1 Background……………………………………………………………………………...01
1.2 Prevalence and Morbidity………………………………………………………….……02
CHAPTER TWO
2.0 Overview of Pancreatic Cancer……………………………………………………..…..04
2.1 The Pancreas…………………………………………………………………...………..04
2.1.1 Exocrine gland……………………………………………………………..……04
2.1.2 Endocrine gland…………………………………………………………....……04
2.2 Types of Pancreatic Cancer…………………………….………………………..……...04
2.2.1 Pre-cancerous growth in the pancreas………………....……..….……………...04
2.2.2 Pancreatic Exocrine Tumours……………………......…………………....……05
2.2.3 Pancreatic Endocrine Tumours…………………………………………............05
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CHAPTER THREE
3.0 Fructose Metabolism and Pancreatic Cancer……………………………………...…….09
3.1 Chemical Structure……………………………………………….……………………..09
3.2 Metabolism…………………………………………………………………………...…09
3.3 Glycolytic Pathway and Pancreatic Cancer…..................................................................13
3.4 The Non-oxidative Pentose Phosphate Pathway…………...…………………………...15
3.5 Uric Acid Production in Pancreatic Cancer……………………………………...……...15
3.6 Effect of Fructose in other cancer cells………………………………………….….......19
3.6.1 Liver Cancer………………………………………………………..………..….19
3.6.2 Breast Cancer……………………………………………………………....…...19
3.6.3 Colon Cancer…………………………………………………………..……..…19
3.6.4 Cancer of the Small Intestine…………………………………….……………..19
CHAPTER FOUR
4.0 Fructose Mechanism in Pancreatic Cancer Cells……………………………….…….....20
4.1 Cancer Mechanisms…………………………………………………………………......20
4.2 Insulin Relation to Pancreatic Cancer Cells………………………………………….....21
4.3 Oxidative Stress, Insulin Resistance and Inflammation in pancreatic cancer………..…21
4.4 Pancreatic Cancer and Diabetes Mellitus….....................................................................26
4.5 Pancreatic Cancer and Obesity……………………………………...……………..……26
4.6 Body Mass Index and Physical Activity in Relation to Pancreatic Cancer…………......27
4.7 Recent Advances in the Role of Fructose Metabolism and Mechanisms in Pancreatic
Cancer Cells………………………………………………...…………………………29
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CHAPTER FIVE
5.0 Dietary Factors in Relation to Pancreatic Cancer………………………………...……..31
5.1 High Fructose Corn Syrup (HFCS) in Relation to Pancreatic Cancer……….………….31
5.2 Fruit and Fruit Juices in Relation to Pancreatic Cancer………………………………...32
5.3 Phytochemicals and Antioxidants in Fruits in Relation to Pancreatic Cancer………….32
5.4 Glucose in Relation to Pancreatic Cancer………………………………………………34
5.5 Other Dietary Factors and Pancreatic Cancer…………………………………………...34
5.5.1 Vegetables………………………………………………………………….…...37
5.5.2 Dietary Meat and Fat…………………………………………..………………..37
5.6 Conclusion……………………………………………………………………………....37
REFERENCES………………………………………………………………………….......39
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LIST OF TABLES AND FIGURES
TABLE
Table 2.1 Differences between benign and malignant tumours…………………………….07
FIGURES
Fig 2.1 Parts of a human Pancreas…………………………………………………………..08
Fig 3.1 Different chemical structures of glucose and fructose……………………………...10
Fig 3.2 Glucose and fructose metabolic pathways in the liver……………………………...11
Fig 3.3 Fructose metabolism in the liver……………………………………………………12
Fig 3.4 Differences in the metabolic pathways of glucose [A] and fructose [B] in pancreatic
cancer cells………………………………………………………………………......16
Fig 3.5 Fructose breakdown in pancreatic cells………………………………………..……17
Fig 3.6 Fructose metabolism to uric acid……………............................................................18
Fig 4.1 The mechanism showing how fructose promotes carcinogenesis and cancer
growth…………………………………………………………………………..…...22
Fig 4.2 The mechanism showing how fructose supports the up regulation of fatty acid
synthesis and the triglyceride synthesis……………………………………...……...24
Fig 4.3 Fructose causes Hepatic Insulin Resistance from the synthesis of triglycerides…...25
Fig 4.4 Potential mechanisms for fructose induced insulin resistance………………….…..28
Fig 5.1 Effect of natural antioxidants on pancreatic cancer………………………………...35
Fig 5.2 Metabolic pathways that are altered by the oncogene Kras………………………...36
viii
SUMMARY
Pancreatic cancer occurs when abnormal cells grow out of control in the pancreas, it is the fourth
leading cause of cancer deaths in the United States. Over the past years, the consumption of
fructose especially in its principal form, High-Fructose Corn Syrup has drastically increased along
as the same time as nutrition-linked chronic diseases. Fructose has been linked to carcinogenesis
and cancer growth of the pancreas. This occurs by the up-regulation of de novo lipogenesis,
reactive oxygen species generation, hepatic insulin resistance, chronic inflammation and cellular
oxidative stress, which can lead to the promotion of deoxy ribonucleic acid damage. Due to the
differences in chemical structure of fructose and glucose, they both exhibit distinct metabolic
properties. Fructose is preferentially used to glucose in the non-oxidative pentose phosphate
pathway that produces ¿85% of ribose for deoxy ribonucleic acid synthesis in cancer cells.
Fructose has similar effects in proliferating human breast cancer, liver cancer cells and other
cancers. Michaud and colleagues reported that fructose may also increase pancreatic cancer risk
in obese or overweight individuals, with a high body mass index, low physical activity and in
susceptible individuals. Although fruits contain high levels of fructose, it is believed that fruits
possess natural antioxidants and phytochemicals, which are thought to inhibit the deleterious
effects of fructose in carcinogenesis. The biochemical mechanisms and the roles of high
consumption of refined fructose in the progression of pancreatic cancers are discussed.
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CHAPTER ONE
INTRODUCTION
1.1 BACKGROUND
The word ‘cancer’ is used to describe any disease in which the cells are abnormal, grow out of control,
and can spread. Thus, pancreatic cancer occurs when abnormal cells grow out of control in the tissue of
the pancreas and form tumour. Tumours are mass of tissues formed from the build up of extra cells.
Tumours may be benign or malignant and just as other living cells they possess the potential for
proliferation, differentiation, cell cycle arrest and apoptosis. Due to this, macromolecule synthesis
pathways directly determine the survival of these cells by providing energy and substrates necessary for
cells to function under different pathophysiologic condition (Boros et al., 2002).
Carbohydrate metabolism through glycolysis and tricarboxylic acid (TCA) cycle is very important for
cancer growth and increased consumption of refined carbohydrate promotes cancer survival. Fructose
stimulates the up regulation of De novo Lipogenesis (DNL), which contributes to cancer risk by
increasing oxidant stress and com- promising cellular antioxidant defense mechanisms (Port et al., 2012).
It does this by increasing depleting NADPH, which is not only required in large amounts for fatty acid
synthesis but is also a major cofactor in maintaining the reduced state level of glutathione and
thioreductase (Port et al., 2012). This is associated with many negative health consequences,
including development of insulin resistance, non alcoholic fatty liver, diabetes, hypertension and kidney
disease, which could increase cancer risk by elevating levels of insulin, glucose, inflammation
and oxidant stress (Port et al., 2012).
Recently, fructose intake contributed directly to oxidative stress in hamster islet tumour cells. It plays a
vital role in the risk of pancreatic cancer and also may act as a marker of high-sugar diet, studies have
shown that pancreatic cancer was inhibited by the drug metformin, which reduces insulin resistance in a
1
hamster pancreatic adenocarcinoma model (Michaud et al., 2002). Also, the studies demonstrated that the
pancreatic ductal cancer either arises from islet cells or from some common progenitor cells that could
give rise to both islet and duct cells (Pour, 1978). Peripheral insulin resistance is associated hyperactivity
and proliferation of islet cells because of this; fructose may be involved in promoting pancreatic cancer
(Michaud et al., 2002).
1.2 PREVALENCE AND MORBIDITY
Pancreatic cancer is the fourth leading cause of cancer related death in the United States (Siegel et al.,
2013). In 2012, it was the twelfth most common cancer worldwide (World Cancer Research Fund
International, 2016). In Japan it is the fifth most common cause of cancer death, preceded in males by
lung, stomach, liver and large bowel, and in females by stomach, large bowel, lung and breast (Lowenfels
and Maisonneuve, 2004). Also, Pancreatic cancer is the 9th most common cancer in Western Europe
and 19th in Middle Africa (World Cancer Research Fund International, 2016).
By 2030, it is expected to be the second leading cause of cancer death. Only 5% of individuals who
develops pancreatic adenocarcinoma survive five years after diagnosis, and most patients live for less
than 12 months (Wolpin et al., 2013). Fructose consumption has increased over the past years and this has
been linked to various diseases including obesity, diabetes, cardiovascular diseases and cancer. The third
National Health and Nutrition Examination Survey reported that over 10% of Americanapolis daily
calories come from fructose of which the largest part comes from sugar sweetened beverages (30%),
followed by grains (22%) and fruit or fruit juices (19%) (Vos et al., 2008). The principal form of this
fructose is the High Fructose Corn Syrup (HFCS, 10-53% glucose and 42-90% fructose) (Tappy et al.,
2010), which has been implicated in pancreatic tumour progression.
2
This review elicits the roles of fructose in pancreatic cancers and other cancers, giving a biochemical
understanding, the implications and ways of managing pancreatic cancers in a developing world.
3
CHAPTER TWO
OVERVIEW OF PANCREATIC CANCER
2.1 THE PANCREAS
The pancreas is an important digestive organ that is about 6 inches long, located deep in the abdomen
between the stomach and the spine (back bone). The liver, intestine, and other organs surround the
pancreas (Figure 2.1). The pancreas is made up of three parts: the head (is closest to the small intestine),
the body (middle section) and tail (the thinnest part).
2.1.1 Exocrine gland makes pancreatic juices, which contains enzymes that help in digestion of food and
releases them into the intestine.
2.1.2 Endocrine gland also known as islet of Langerhans make important hormones, such as insulin and
glucagon and release them directly into the bloodstream.
2.2 TYPES OF PANCREATIC GROWTH
2.2.1 Pre-cancerous growth in the pancreas
Serous cystic neoplasm (also known as Serous Cystadonomas): they are usually benign tumours that have
sacs (cyst) filled with watery fluid.
Mucinous cystic neoplasm (also known as Mucinous Cystadonomas): they are slow growing tumours in
the body or tail of the pancreas that have cyst filled with a jelly-like substance called mucin.
Intraductal papillary mucinous neoplasm: are benign tumours, which make mucin that grow in pancreatic
ducts
4
2.2.2 Pancreatic Exocrine Tumours
Exocrine cancer is the most common type of pancreatic cancer. More than nine out of ten people (95%)
have this type. They include:
Pancreatic adenocarcinoma: 95% of pancreatic cancer type is the pancreatic adenocarcinoma. They
usually begin in the ducts (gland cells) of the pancreas but sometimes they develop from the cells that
make the pancreatic enzymes in which case they are called acinar cell carcinomas.
Solid pseudopapillary neoplasm: these are rare, slow growing tumours that almost always occur in young
women.
Less common type of cancer: adenosqua carcinomas, squamous cell carcinomas, signet cell carcinomas,
different carcinomas and undifferentiated with giant cells.
Ampullary cancer (carcinoma of the ampulla of vater): this cancer starts at the ampulla of vater which is
where the bile ducts and pancreatic duct come together and empty into the small intestine.
2.2.3 Pancreatic Endocrine Tumours
They include:
a) Functioning tumours: they make hormones that are released into the blood and cause symptoms
Gastrinomas: about half of gastrinomas are cancers. It comes from cells that make gastrin.
Insulinomas: most insulinomas are benign. It comes from cells that make insulin.
Glucagonomas: most glucagonomas are cancers. It comes from cells that make glucagon.
Somatostatinomas: most somatostatinomas are cancerous. It comes from cells that make somatostatin.
VIPomas: most VIPomas are cancerous. It comes from cells that make Vasoactive Intestinal Peptide
(VIP).
PPomas: most PPomas are cancerous. It comes from cells that make Pancreatic Polypeptide (PP).
5
b) Non functioning tumours: they are more likely to be cancerous than functioning tumours because these
tumours does not make enough excess hormones to cause symptoms, they can grow quite large before
they are found.
c) Carcinoid tumours: they rarely start in the pancreas, although they are much common in other parts of
digestive system. This tumour often makes serotonin (also called 5-HT) or its precursor 5-HTP.
Note: metastasis is when cancer cells often travel to other parts of the body, where they begin to grow and
form new tumours that replace normal tissue. It happens when cancer cells get into the lymph nodes or
bloodstream of the body. Tumours can be either malignant or benign. Table 2.1 shows a comparison
between malignant and benign tumours.
6
Figure 2.1 Parts of a human pancreas (National Cancer Institute, 2010).
7
Table 2.1. Differences between benign and malignant tumours
Benign Tumours (e.g. cyst) Malignant Tumours
They are usually not a threat to life. They may be a threat to life.
They can be removed and usually
don’t grow back.
They are removed sometimes, but can
grow back.
They don’t invade the tissues around
them.
They can invade and damage nearby
tissues and organ.
They don’t spread to other parts of
the body.
They can spread to other parts of the
body.
8
CHAPTER THREE
FRUCTOSE METABOLISM AND PANCREATIC CANCER
3.1 CHEMICAL STRUCTURE
Although glucose and fructose have identical chemical formulas (C6H1206) (figure 3.1), the difference in
their chemical structure result in completely distinct absorptive and metabolic properties, which have
fundamental implications for cellular functions and disease (Varman, 2011).
3.2 METABOLISM
The disaccharide (i.e. sucrose) components of the food we consume are cleaved in the gut into smaller
glucose and fructose units. Fructose is absorbed in the small intestine by the fructose specific transporter,
glucose transporter 5 (GLUT5) while glucose is absorbed through the gut by sodium-dependent glucose
transporter (Bray, 2013). The liver is the major site of metabolism, which removes up to 70% of the portal
fructose, leaving the 30% for metabolism by other tissues (kidney, musculoskeletal, testes, fat and brain).
In contrast, the glucose is transported to hepatocytes and most other cell types using the glucose specific
insulin-dependent transporter, GLUT4 (figure 3.2). Once in the hepatocytes, some of the glucose is
absorbed while others goes into glycolysis and other metabolic pathways. During elevated concentration
of glucose the pancreatic hormone, insulin, is released from the beta cells to regulate the glucose levels in
the bloodstream. It should be noted that GLUT5 does not respond to insulin, thus leaving fructose uptake
uninhibited. Fructose is independent of insulin and uses GLUT5 transporter, while glucose is regulated by
insulin and uses the GLUT4 transporter (Charrez et al., 2015).
Figure 3.3 shows that a small amount of fructose goes into gluconeogenesis for the immediate production
of glucose. The green pathway is related to the phosphorylation of fructose by fructokinase and the by-
product of this is uric acid. Down to the left is an aldehyde pathway, which is the concept, used for the
production of alcohol. The yellow pathway leads to the production of Insulin receptor substrate-1 (IRS-1),
9
Figure 3.1 Different chemical structures of glucose and fructose (A) The hemiacetal group of glucose is
substituted to a hemiketal group for fructose. (B) Representation of the open ring structure of glucose and
fructose (Charrez et al., 2015).
10
Figure 3.2 Glucose and fructose metabolic pathways in the liver (Charrez et al., 2015).
11
Figure 3.3 Fructose metabolism in the liver (http://www.nofructose.com/introduction/metabolism/
Sourced on 08/05/2016).
12
which is important in the chemical feedback of insulin and the pancreas. The blue pathway effectively
shows the conversion of fructose into Very Low Density Lipoproteins (VLDL’s).
3.3 GLYCOLYTIC PATHWAY AND PANCREATIC CANCER
Glycolysis makes available substrates needed for the nonoxidative pentose phosphate pathway and other
metabolic pathway in the body. It should be noted that the pyruvate kinase isoform, PKM2, that catalyse
the reaction of phosphoenol pyruvate to pyruvate is only expressed in tumour cells. Due to its low
enzymatic activity it slows down pyruvate formation thus leading to the accumulation of upstream
intermediates, thereby increasing substrate available for the non-oxidative pentose phosphate pathway.
Some biotechnologist recognised that as glucose utilization increases, so does lactate production from
anaerobic glycolysis, which limits growth as pH becomes increasingly acidic (Port et al., 2012). This is
the same challenge cancer cells face. Substituting fructose into culture media limits growth, but
simultaneously decreases lactate levels and into culture media limits growth, but simultaneously
decreases lactate levels and increases protein yields, suggesting that once inside cells, fructose
derived carbons are directed away from glycolysis and into pathways that generate metabolites used for
protein synthesis (Port et al., 2012).
3.4 THE NON-OXIDATIVE PENTOSE PHOSPHATE PATHWAY AND PANCREATIC
CANCER
The non-oxidative pentose phosphate pathway (PPP) which involves the conversion of a six carbon
glucose to a five carbon ribose for deoxy ribo nucleic acid (DNA) and ribo nucleic acid (RNA) synthesis
is of utmost importance for the proliferation process and produces >85% of the ribose recovered from
tumour nucleic acids. The non-oxidative PPP is controlled by transketolase (TK) enzyme reactions which
is encoded by three human TK genes, namely: TKT, TKTL1 and TKTL2. Clinically, there is a tendency
13
for patients with cancer burden to develop thiamine depletion, which is a cofactor for TK-mediated
reaction, thus emphasizing the importance of the non-oxidative Pentose Phosphate Pathway for tumour
growth (figure 3.4). There is a preferential use of fructose in the TK-dependent nonoxidative pentose
phosphate shunt, while glucose is used mainly for glycolysis, TCA cycle, glycogen synthesis, lipid
synthesis, amino acid synthesis (nonessential). Thus, leaving a small percentage of glucose for the
pentose phosphate shunt. (Liu et al., 2010).
From the study and data analysis made by Liu et al. (2010) the contribution of fructose to nucleic acid
synthesis is considerably greater than glucose. They studied the effect of protein synthesis in pancreatic
cancer cell lines (Panc-1, MiaPaCa-2, HPAF, CaPan-1) and immortalized pancreatic ductal cells
(HPDE6; Port et al., 2012), and later discovered that fructose is preferentially used in cancer calls through
transketolase (TKT)-mediated metabolism to synthesize additional nucleic acid to facilitate proliferating
capacity. In their study the transketolase-like protein 1 (TKTL-1) was overexpressed in pancreatic cancer
when compared to normal tissue, but the TKT mRNA was the predominant expressed TK gene in
pancreatic cancer cells. Figure 3.5 shows the breakdown of fructose, and that fructose treatment in
pancreatic cell lines preferentially increased nucleotide synthesis. It does this by up regulating expression
of transketolase (TKT) leading to increased flux in pentose phosphate shunt (Port et al., 2012).
Also, Fructose-1-6-phosphate allosterically activates PKM2 through inducing the tetramer formation of
PKM2 (Xu et al., 2016). This lead to the accumulation of Fructose-6-phosphate during TKT knockdown,
which later resulted in the activation of PKM2, leading to the decrease of aerobic glycolysis and a
reduction of lactate accumulation (Xu et al., 2016) (Figures 3.4 and 3.5).
In contrast, Xu et al. (2009) reported that the strong proliferation of tumour cells is governed by the
replication of DNA in the S phase where the conversion of glucose to ribose is controlled by non-
14
oxidative PPP. They discovered by flow cytometry that TKLT-1 showed slower growth rates when cell
cycle was arrested in G0/G1 phase.
3.5 URIC ACID PRODUCTION IN PANCREATIC CANCER
Excess fructose is hazardous for the body because it causes hyperuricaemia due to the accumulation of
adenosine diphosphate (ADP) and adenosine monophosphate (AMP). Dietary fructose when absorbed by
the body is the only sugar that raises the uric acid concentration in the blood (Nakagawa et al., 2006).
Ketohexokinase (KHK) is insulin and citrate independent which permits the phosphorylation of fructose
to Fructose-1-phosphate in the liver and this reaction occurs rapidly without any feedback inhibition (Vos
et al., 2013). The phosphate molecule required for this reaction comes from the depletion of adenosine
triphosphate (ATP) (Figure 3.6).
ATP is the molecule involved in energy transfer within cells, the phosphate group within it, is depleted
following the metabolism of Fructose by Hexoketokinase. The decrease in intracellular phosphate
stimulates adenosine monophosphate deaminase (AMP D) which catalyses the degradation of adenosine
monophosphate (AMP) to inosine monophosphate and eventually uric acid (Johnson et al., 2013).
Fructose promotes the production of uric acid, which is a by-product of nucleotide (purine) metabolism
through the non-oxidative PPP (Charrez et al., 2015). Uricase activity (which correlate closely with uric
acid production) that was measured in pancreatic cancer cells, they found out that fructose-treated cells
resulted in 20%, and 50% higher uricase activity in the cancer cells than glucose-treated cells. This study
shows that fructose is preferentially utilized for nucleic acid synthesis (Liu et al., 2011).
15
Figure 3.4. Differences in the metabolic pathways of glucose [A] and fructose [B] in pancreatic cancer
cells (Liu et al., 2010).
16
Figure 3.5. Fructose breakdown in pancreatic cells (Port et al., 2012).
17
Figure 3.6 Fructose metabolism to uric acid. (http://www.nofructose.com/introduction/metabolism/
Sourced on 08/05/2016).
18
3.6 EFFECTS OF FRUCTOSE IN OTHER CANCER CELLS
3.6.1 Liver Cancer
A study reported that liver tumour was found to be two fold greater with increased metastasis, and
reduced survival in rats treated with N-nitrosormorpholine for 7 weeks and subsequent fructose
frequently. Moreover, the authors also observed that the fructose increased the number of preneoplastic
lesions by 26% (Charrez et al., 2015). TkT enzyme in the non-oxidative pentose phosphate pathway was
found to be the most predominant enzyme in hepatocellular carcinoma (HCC). This enzyme was over
expressed, which lead to venous invasion, tumor microsatellite formation, tumor size, and absence
of tumor encapsulation. (Xu et al., 2016).
3.6.2 Breast Cancer
The GLUT 1 and GLUT 2 were found to be present in both normal and neo-plastic breast cancer
(Zamora-Léon et al., 1996). But GLUT 5, which is the fructose transporter, was found to be over
expressed human breast cancer and was absent from normal breast tissue (Zamora-Léon et al., 1996).
GLUT 5 transports fructose with high affinity while GLUT 2 does not. This shows that fructose may have
an effect in proliferating human breast cancer cells.
3.6.3 Colon Cancer
In a study, males with high intakes of dietary glycaemic load: fructose and sucrose resulted in a
significant 27% - 37% increase in colorectal cancer. However, for women, these factors did not lead to an
increase in colorectal cancer (Michaud et al., 2005).
3.6.4 Cancer of the Small Intestine
Banzzan et al. (2013) reported that fructose intake that is associated with obesity has been shown to be
used preferentially in the proliferation of cancer cells of the small intestine.
19
CHAPTER FOUR
FRUCTOSE MECHANISM IN PANCREATIC CANCER CELLS
4.1 CANCER MECHANISMS
Cancer is not a single disease with a single aetiology, but is rather a general disease category that includes
many distinct diseases with distinct aetiologies (Terry et al., 2001). Carcinogenesis is a multistep process
and oxidative damage has been linked to the formation of tumours. Free radicals due to oxidative stress
can cause DNA damage, which, when left unrepaired, can lead to base mutation, single and double strand
breaks, DNA cross-linking, and chromosomal breakage and rearrangement (Liu, 2003). These mutations
caused on the DNA by free radicals are crucial for the initiation of the carcinogenesis process (Zhang et
al., 2015) (Figure 4.1).
Catabolic and anabolic metabolism has a role in furnishing biochemical energy and building blocks for
macromolecular synthesis and repair, these metabolic pathways are vital to cancer cell growth and
survival in different tumour microenvironments (Hockenbery et al., 2013). In recent studies, metabolic
pathway can also direct chromatin structure and gene expression, differentiation and steaminess, which is
also associated with increased histone methylation and altered gene expression (Hockenbery et al., 2013).
In a recent study, after the incubation of Escherichia coli plasmid PBR322 for 15 days with fructose and
glucose phosphates metabolites, it resulted in variety of DNA modifications and damage (Liu and Heaney
2011). The intensity of the damage done is in the following order: glucose-1-phosphate < glucose <
glucose-6-phosphate < fructose-1-phosphate < fructose < fructose-6-phosphate (Liu and Heaney 2011).
This result gotten supports the hypothesis that fructose intake may cause cancer growth and also help in
proliferation of cancer cells.
20
4.2 INSULIN IN RELATION TO PANCREATIC CANCER
Insulin is produced by the β cells of the pancreas in response to elevated glucose levels. In humans with
normal glucose metabolism, 85% to 94% of the variability of postprandial glucose and insulin responses
can be explained by both the source and the amount of carbohydrate intake (Wolever and Bolognesi,
1996). In addition, Insulin can promote tumor development by inhibiting apoptosis and stimulating cell
proliferation (Nöthlings et al., 2007). It has been observed that insulin acts as a promoter for pancreatic
carcinogenesis (Michaud et al., 2005). It should also be noted that growth factor like insulin is used for
mucosal cells in vitro growth by up regulating systematic insulin-like growth factor (IGF)-I activity (Jiao
et al., 2009). High serum levels of IGF-I and IGFBP-3 were associated with an increased risk of death
from pancreatic cancer (Jiao et al., 2009).
4.3 OXIDATIVE STRESS, INSULIN RESISTANCE AND INFLAMMATION IN PANCREATIC
CANCER
Oxidative stress, insulin resistance and inflammation have been linked to the cause of various chronic
diseases, like: cancer and cardiovascular diseases. Fructose leads to an elevated production of uric acid,
this uric acid enters into the cells through the specific organic anion transporter, which induces an
oxidative stress that has been shown in vascular smooth muscle cells, endothelial cells, adipocytes, islet
cells, renal tabular cells and hepatocytes (Johnson et al., 2013). This oxidative stress can cause oxidative
damage to large biomolecules such as proteins, DNA, lipids, resulting in increased risk of cancer and
cardiovascular diseases (Liu, 2013).
In addition, rat treated with fructose led to hyper insulinaemia, insulin resistance, impaired glucose
tolerance, increased thymidine incorporation and decreased endothelium Nitric Oxide Synthase (eNOS)
activity (Miatello et al., 2001). Uric acid is a potent inhibitor of Nitric Oxide synthase, which later affect
21
Figure 4.1 the mechanism showing how refined fructose promotes carcinogenesis and cancer growth (Liu
and Heaney, 2011).
22
the Nitric Oxide activity, and thus leads to oxidative stress within various cells especially Adipocytes (fat
cells). Also, uric acid-induced oxidative stress is mediated by the stimulation of NADPH Oxidase, which
translocate in the liver and generates oxidized lipids and inflammatory mediators such as Monocyte
Chemoattractant Protein-1 (MCP-1). This mitochondrial oxidative stress has a role in driving insulin
resistance (Lanaspa et al., 2012).
Due to the oxidative stress caused by uric acid in the mitochondria, there is a decrease in the activity of
aconitase (ACO2) in the kerb cycle. This leads to the accumulation of aconitase substrate and citrate,
which are released to the cytosol, where they act as substrate for triglyceride (TG) synthesis through the
activation of ATP Citrate Lyase (ACL). Large amount of fructose expressed in the liver leads to
lipogenesis, triglyceride accumulation, reduced insulin sensitivity and hepatic insulin resistance/glucose
intolerance. It supplies substrates like: glycerol-3-phosphate and Acyl-CoA for De novo Lipogenesis that
can later lead to hepatic insulin resistance (Figure 4.2 and 4.3).
It should also be noted that inflammation is associated with high level of oxidative stress that can damage
most of the body tissues and the genetic material (DNA), which lead ultimately to cancer formation
(Banzzan et al., 2013).
In a large, nested case control study, the mutual adjustment of peripheral insulin resistance marker,
hyperglycaemia or pancreatic cells dysfunctions were associated with pancreatic adenocarcinoma
(Wolpin et al., 2013). This finding highlights the association between type II diabetes mellitus, obesity
and pancreatic adenocarcinoma risk and might suggest the correction of insulin resistance as a preventive
strategy (Pericleous et al., 2014) (Figure 4.4).
23
Figure 4.2 the mechanism showing how fructose supports the up regulation of fatty acid synthesis and the
triglyceride synthesis (Johnson et al., 2013).
24
Fig 4.3 Fructose causes Hepatic Insulin Resistance from the synthesis of triglyceride (Basciano et al.,
2005).
25
4.4 PANCREATIC CANCER AND DIABETES MELLITUS
Chronic administration of fructose or sucrose to animals did not only cause insulin resistance but also
resulted to the development of type II diabetes. In tissue studies, the pancreatic islets show hyalinosis and
macrophage infiltration, similar to what is observed in humans having type II diabetes. The mechanisms
of how fructose induces this changes is not known, because the GLUT 5 transporter which is the primary
transporter of fructose is not expressed in the islet cells. However, Johnson et al. (2013) reported an up
regulation of the Urate transporter (URAT-1) in islet of fructose fed rats in association with increased
expression of MCP-1. Also, the incubation of cultured insulin secreting with uric acid lead to oxidative
stress and synthesis of MCP-1. This oxidative stress in islet cells is considered to have a major role in
causing the pancreatic islet dysfunction in type II diabetes.
4.5 PANCREATIC CANCER AND OBESITY
Obesity rates have doubled since 1980 and 2014 (World Health Organization, 2016). In 2014, 13% of the
World’s adult population were obese (World Health Organization, 2016). This obesity has been linked to
other health consequences including: cardiovascular diseases (mainly heart and stroke, which were the
leading cause of death in 2012.), diabetes, muscoskeletal disorders (osteoarthritis) and some cancers.
Obesity is caused by an imbalance between calorie intake (increase in high carbohydrate diet), and a
sedentary lifestyle.
The consumption of sugar and fructose as sweeteners with low sodium and fat intake has increased as the
same time as nutrition-linked chronic diseases have reached epidemic proportions in humans. This
increased consumption of sweetened foods and beverages expose the human body to high amounts of
fructose than those that naturally occur in fruits and vegetables. Also, the correlation to chronic diseases
has lead to the implications that excess fructose is involved in developing insulin resistance and also
obesity (Dekker et al., 2010). Fructose tends to behave more like fat than other carbohydrate in respect to
26
insulin resistance, leptin production, and post prandial TG levels. It also does not cross the brain barrier
and could potentially contribute to increase energy intake. Studies in humans have reported weight gain
during prolonged fructose consumption (Teff et al., 2004).
4.6 BODY MASS INDEX AND PHYSICAL ACTIVITY IN RELATION TO PANCREATIC
CANCER
Body Mass Index (BMI) is an approximate measure of whether someone is over- or under weight,
calculated by dividing their weight in kilograms (kg) by the square of their height in metres (m2).
Glycaemic Index (GI) is an empirical measure of blood glucose response after consumption of a specific
food (Nöthlings et al., 2007). While Glycaemic Load (GL) is the GI of a food multiplied by its
carbohydrate content, which reflects both the quantity and quantity of dietary carbohydrates, consumed
(Michaud et al., 2002). The Body Mass Index and physical activity were two factors considered in a
cohort study of US women in relation to the risk of pancreatic cancer. They observed that among women
with high compared with those with low glycaemic load or glycaemic index scores, there was a consistent
although not a significant increase in pancreatic cancer risk when BMI was high (≥25kg/m2) (Michaud et
al., 2002). In contrast, glycaemic load or glycaemic index did not increase the risk of pancreatic cancer in
these women who had BMIs of less than 25kg/m2.
In addition, they also found out that fructose intake was associated with an elevated risk of pancreatic
cancer among women who were obese but not among lean women. Similarly, there was a statistically
significant increase of 86% of pancreatic cancer risk in inactive women with either high or low fructose
intake. In a multi-ethnic cohort study, the physical activity was not a factor in determining the risk of
pancreatic cancer, but they found an elevated risk in pancreatic cancer with participants that consumed
fructose who were obese/overweight (Nöthlings et al., 2007).
27
Figure 4.4 Potential mechanisms for fructose-induced insulin resistance (Tappy and Lê, 2010).
28
4.7 RECENT ADVANCES IN FRUCTOSE METABOLISM AND MECHANISM IN
PANCREATIC CANCER CELLS
In the 1920s, Otto Warburg observed that some proliferating tissues, especially tumour cells, display
glucose uptake, and even in the presence of oxygen preferentially metabolise glucose-derived pyruvate to
lactate. This phenomenon of aerobic glycolysis is known as the ‘Warburg Effect’ (Cohen et al., 2015).
However, some biotechnologist recognise that as glucose utilization increases, so does lactate production
from anaerobic glycolysis, which limits growth as pH becomes increasingly acidic (Port et al., 2012).
This is the same challenge cancer cells face. Substituting fructose into culture media limits growth, but
simultaneously decreases lactate levels and increases protein yields, suggesting that once inside cells,
fructose-derived carbons are directed away from glycolysis and into pathways that generate metabolites
used for protein synthesis (Port et al., 2012).
In addition, the knockdown of TKT in the non-oxidative PPP drastically reduced tumour growth
regardless tumor growth regardless of the accumulation of ribose intermediates suggesting that ribose was
not a limiting factor in cancer growth (Xu et al., 2016).
On the other hand, TKT knockdown resulted in a decrease of NADPH and an increase of ROS, further
suggesting that oxidative stress homeostasis is an important determining factor in cancer growth (Xu et
al., 2016).
Also, current observation was made that the mean circulating fasting fructose levels in pancreatic cancer
cells were 2.5 fold higher in comparison with fasting fructose level in healthy patient. The role of fructose
to generate nucleic acids is supported by the demonstration of elevated production of uric acid, as a by-
product of purine metabolism and this provides important mechanistic insight into a recent report of
increased serum uric acid levels in patients with high fructose consumption (Charrez et al., 2015).
29
Furthermore, hyperinsulinaemia; metabolic syndrome and type II diabetes mellitus have all been
associated with pancreatic cancer (Pericleous et al., 2014). Interestingly, the drug metformin that is used
to treat diabetes appears to reduce pancreatic cancer (Pericleous et al., 2014).
Finally, fructose is the only sugar that raises uric acid concentration in the blood. Serum uric acid
concentration has been shown to have a strong positive association with the risk of pancreatic cancer
mortality in men (Jiao et al., 2009).
30
CHAPTER FIVE
DIETARY FACTORS IN RELATION TO PANCREATIC CANCER
Dietary factors have been thought to account for about 30% of cancers in Western countries, thus making
diet second only to tobacco smoking as a preventable cause of cancer. Diet contribution to cancer risk in
developing countries has been considered to be lower, perhaps around 20%. Therefore, unravelling the
effects of diet is of great public importance (Key et al., 2004).
5.1 HIGH FRUCTOSE CORN SYRUP (HFCS) IN RELATION TO PANCREATIC CANCER
High Fructose Corn Syrup (HFCS) is the most preferred used sweetener, which is found in processed
foods, baked goods, condiments, soft drinks, candy, dairy products and concentrated fruit juices (Bray,
2013). The consumption of this principal form of fructose has increased as the same time with most
common human disease (including: obesity, diabetes, cardiovascular diseases and cancer).
In a prospective study conducted, a significantly greater risk of pancreatic cancer associated in both men
and women with high consumption of added sugar, soft drinks, and sweetened fruit soups or stewed fruit
was observed than low consumption of those items (Larsson et al., 2006). Also, no association was found
between the consumption of jam or marmalade or sweets and pancreatic cancer risk. They reported that
in a case control study, women with high intake of added sugars had a 3.7 times greater risk of pancreatic
cancer than those who had low intakes, but this association with high intake was not significant in men. In
a cohort study conducted by Michaud et al. (2002), they observed that the strongest risk of pancreatic
cancer was associated with fructose intake. Foods that contribute to this dietary fructose (as a
monosaccharide) include: soda, punch, and fruit juices, which accounts for a higher percentage of dietary
glycaemic load.
31
Furthermore, in two prospective cohort work done by Schernhammer et al. (2005), they failed to find a
significant overall association between sweetened soft drinks and pancreatic cancer. Although, the data
they got may suggest a modesty higher pancreatic cancer risk in both sedentary and overweight women
who had high consumption of sweetened sugar and soft drinks.
5.2 FRUIT AND FRUIT JUICES IN RELATION TO PANCREATIC CANCER
Fructose which is fruit sugar, is a simple ketogenic monosaccharide found in many plants, where it is
often bonded to glucose to form the disaccharide sucrose. For the past years fruits have been known to
stop or fight against different human disease. From this two study carried out, their findings may question
the benefits of fruit we are meant to believe in. In a multi-ethnic study conducted by Nöthlings et al.
(2007), they found an association of pancreatic cancer risk with obese men not in obese woman who had
a high consumption of fruit juices and not with high intake of soda. A prospective cohort study conducted
by Jiao et al. (2009), reported a greater risk of pancreatic cancer from free fructose in fruits and fruit
juices than from other sources (including: soda and soft drinks). The analysis showed that fruits but not
fruit juices were associated with a greater risk of pancreatic cancer.
5.3 PHYTOCHEMICALS AND ANTIOXIDANTS IN FRUITS IN RELATION TO PANCREATIC
CANCER
Phytochemicals are simply the bioactive non-nutrient plant components in fruit, vegetables, grains and
other plant foods. These phytochemicals and antioxidants could inhibit cell proliferation and induce
cancer cell death. Johnson et al. (2013), reported that natural fruit contain numerous substance that can
block the effect of fructose including: potassium, vitamin C and antioxidant such as: resveratrol, quercetin
and other flavonols. Where as fructose from added sugars is linked with hypertension, fructose from
natural fruit is not.
32
In a recent study, reported by Pericleous et al. (2014), citrus fruits (orange, tangerine, lime, lemon and
grape fruit) are rich in flavonoids such as hesperidin, rutin and diosmin, which have been shown to have
antitumor, anti-proliferative and pro-apoptotic properties. They are also rich in carotenoids such as β-
carotene and lutein that may also decrease the risk of cancer (Martí et al., 2009). Citrus fruits also contain
citrus limonoids compounds such as limonin and nomilin that were found to possess antioxidant and
anticancer properties (Patil et al., 2010). Bennett et al. (2012) reported that several clinical trials using
antioxidants and natural compounds have been conducted to observe if this compounds have anticancer
and chemo preventive properties. Compounds such as selenium, Vitamin E, and carotene have been
shown to exhibit pharmacologic and biologic effects as anticancer agents.
Although, dietary supplement does not have the same effect as natural fruit. He explained that the natural
combination of phytochemicals in fruits and vegetables is responsible for the potent antioxidant (Liu,
2003). This was achieved by using the effect of apple extract with skin that reduced tumour growth
compared with apple extract without skin.
Nutrients commonly found in fruits and vegetables have been inversely associated with several other
cancers including pancreatic cancer (Chan et al., 2005). Potential mechanisms of action include
antioxidant protection against free-radical damage to DNA and polyunsaturated fats (e.g., vitamin C,
carotenoids, tocopherols, and selenium), apoptosis ((e.g., indole-3 carbinol in cruciferous vegetables),
enhancing immune function (e.g., carotenoids, vitamin C, and vitamin E), modulating hormonal pathways
linked to cancer, such as sex hormones (e.g., soy and lignans) or insulin-like growth factor (e.g.,
lycopene), inhibiting cellular proliferation (e.g., carotenoids), and ensuring proper DNA methylation and
gene expression (e.g., folate; Chan et al., 2005).
33
5.4 GLUCOSE IN RELATION TO PANCREATIC CANCER
Pancreatic ductal adenocarcinoma (PDA) exhibits an elevated capacity for glucose uptake (Sousa et al.,
2014). This metabolic changes involving glucose are driven by the oncogenic Kras (Sousa et al., 2014).
Figure 5.2 shows enzymes whose expression is increased by Kras are indicated with an asterisk. Increased
glucose uptake fuels glycolysis (leading to increased lactate production), anabolic pathways such as the
non-oxidative arm of the PPP (producing ribose for nucleotide biosynthesis) and the HBP (producing
precursors for glycosylation) (Sousa et al., 2014). Glutamine is a key metabolite that is utilized to fuel the
TCA cycle and maintains redox homeostasis in PDA through a novel pathway (shown in orange) that
leads to NADPH production (Sousa et al., 2014).
Also, the consumption of high-sugar foods may increase the risk of pancreatic cancer by the direct effects
of increased glucose concentrations. This chronic excess of glucose had toxic effects on the pancreatic
islet and may result in beta cell dysfunction and eventually cell death, a phenomenon regarded as ‘glucose
toxicity’. One of the potential central mechanisms for glucose toxicity is the increased formation of
reactive oxygen species (ROS), when in prolonged excess can cause chronic oxidative stress (Robertson,
2004).
5.5 OTHER DIETARY FACTORS AND PANCREATIC CANCER
5.5.1 Vegetables
People who consumed at least five servings of vegetables per day were inversely associated with the risk
of developing pancreatic cancer than those who did not. Specifically, dark leafy vegetables, cruciferous
vegetables, yellow vegetables, beans, onions, garlic and carrots were found to be associated with reduced
risk of pancreatic cancer (Chan et al., 2005).
34
Antioxidants in Pancreatic
Cancer
DNA damage (vit. C, carotenoids, tocopherols &
selenium)
Apoptosis (indole-3 carbinol)
Enhance immune function
(carotenoids, vit. C & vit. E)
Modulate hormonal
pathway (soy & lignans)
Modulate insulin-like growth facor
(lycopene)
Inhibit cellular proliferation (carotenoids)
Ensure proper DNA methylation
& gene expression
(folate)
Figure 5.1 Effect of natural antioxidants on pancreatic cancer (the purple circle). The red circles represent
what happens to the cancer cells while the blue circles represent the mechanisms taken to fight the cancer
cells.
35
Figure 5.2 Metabolic pathways that are altered by the oncogene Kras (Sousa et al., 2014).
36
Raw vegetables may impart more benefit than cooked vegetables due to their potential increased nutrient
content, lower glycemic index, higher level of enzymes important for phytochemical production, and
increased insoluble fiber content (Chan et al., 2005). In addition, a study done on anti proliferative and
antioxidant activities of common vegetables identified a number of cruciferous and allium vegetables as
foods with exceptional inhibitory activity against tested cancer cell lines, including pancreas and kidney.
The vegetables found to possess very potent inhibitory activities include: garlic, leak, immature green
onion, Brussels sprouts, kale, broccoli and various cabbages (Boivin et al., 2009).
5.5.2 Dietary Meat and Fat
In a large cohort of women, there was no association found between the intake of meat, dairy products,
fat, cholesterol and the risk of pancreatic cancer (Michaud et al., 2003). Rodents fed high-fat
diets experienced a greater incidence of pancreatic tumors than did rodents fed low-fat diets with a similar
caloric content (Michaud et al., 2003). In one study, rodents fed diets rich in saturated fat and also linoleic
acid had the greatest increase in pancreatic tumorigenesis (Michaud et al., 2003). It has been suggested
that the different practices of cooking or processing meat may be related to the risk of pancreatic cancer
(Michaud et al., 2003). Cooking meat at high temperatures can result in the formation of heterocyclic
amines, and processing meats (e.g., curing or smoking) increases N-nitroso compounds (Michaud et al.,
2003). In a case-control study in China, intake of deep-fried foods was not associated with pancreatic
cancer risk, but smoked and cured foods increased the risk of pancreatic cancer (Michaud et al., 2003).
5.6 CONCLUSION
Taken together, fructose consumption has increased over the past years especially in its principal form;
High-Fructose Corn Syrup (HFCS). This has been linked to the epidemiology of different human diseases
such as obesity, diabetes and cancer. This simple sugar with the same chemical formula as glucose has a
different metabolism from that of glucose. It is believed that the antioxidants and phytochemicals in fruits
37
inhibit the effect of fructose to promote carcinogenesis and cancer growth. Therefore, more research is
required in this area of study to ascertain the role played by fructose in carcinogenesis and cancer growth
in HFCS or in its natural form.
38
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