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Cancer and Apoptosis combined
An historical introduction
Mathieu Noteborn
LIC, Leiden University, NL
LC Workshop - 29 October 2007
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Cancer and Apoptosis combinedAn historical Introduction
Apoptosis versus cancer
Viruses inducing Cancer: lessons to be learned
Proteins killing tumor cellsApoptin E4orf4 HAMLET MDA7 NS1 TRAIL
A brief preview to our workshop
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Apoptosis and lifebelong together
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Apoptosis is a genetically regulatednetwork of pathways
Factors can “positively or negatively” interfere with apoptosis machinery
Imbalances in apoptosis pathwaysunderlie many different diseases
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West Nile virus induces apoptosis in brain cells resulting in meningitis/encephalitis
Inhibition of apoptosis resultsin tumor cell formation
Interference in apoptosis machinery
Induction Inhibition
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Interference at various steps in the apoptotic machinery results in tumor formation
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“Living with p53, dying of p53”
Aylon & Oren, 2007
Mutated p53/partners might result in genetic instability/cancer
Cellularbackground
Cellularbackground
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Up-regulation of anti-apoptotic proteins results in tumor formation
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Bcl-2/BclXl form dimers via their BH3 domainswith each other or with pro-apoptotic family members
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EpiGalleCatechin Gallate; EGCG
Reed, 2006
Prevention of formation of anti-apoptotic Bcl-2 homo- or hetero-dimers results in killing of tumor cells
anti-apoptotic proteins as Bcl-2 are potential drug targets
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Expression of Livin causes chemo-resistance of tumor cells
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Liu et al., 2007
Down-regulation of Livin sensitizes tumor cells to chemotherapeutic drugs
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Aberrancies in Bcl-2, p53 & Fas: tumor “beats” our defense mechanism
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Apoptosis versus CancerSummary
Defects in apoptosis pathways
Contribute to cancer
Permitting aberrant cell behavior
Desensitizing tumor cells to:Immune-mediated attack Chemotherapy
Cancer development and anti-cancer therapy
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Cancer and Apoptosis combinedAn historical Introduction
Apoptosis versus cancer
Viruses inducing Cancer: lessons to be learned
Proteins killing tumor cellsApoptin E4orf4 HAMLET MDA7 NS1 TRAIL
A brief preview to our workshop
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DNA tumor virusesPapilloma virusAdenovirusHerpesvirusEpstein Barr virusHepatitis B virusPolyoma virus
SV40
RNA tumor virusesRetroviruses
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SV40 transforms cells
SV40 LT interacts with tumor suppressor p53
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DNA-tumor viruses express proteins interferingwith cellular factors resulting in cellular transformation
O’Shea, 2004
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SV40 LT and st have transforming activities
LT interactswith e.g. p53, Rb
st interacts withPP2A
Pipas
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PP2A-dependent pathways targeted by SV40 stcontributes to cell transformation
Sontag & Sontag, 2006Arroyo
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…. and most likely muchmore gene products areaffected by st synthesis
Affymetrix studies
SV40 st affects e.g.expression of factorswithin the Wnt, Hedgehog& Notch pathways
Ali-Seyed et al., 2006
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SV40 st affects Apoptosis PathwaysDown-regulation expression of pro-apoptotic factorsUp-regulation expression of anti-apoptotic factors
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DNA tumor viruses & apoptosis
SV40 transforming LT and st Inhibition of pro-apoptotic processes (p53/caspase)Stimulation of anti-apoptotic processes (survivin)
Adenovirus proteinsInhibition of pro-apoptotic processesStimulation of anti-apoptotic processes?
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White, 2006
Transforming adenovirus inhibits and induces apoptosis
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SV40 LT/st inhibits apoptosis
Adenovirus E1B proteins inhibit apoptosisAdenovirus E1A induces apoptosis
Why does transforming adenovirus harbor E1A protein?Apoptosis is an essential step in (Ad) transformation?
NextOncolytic viruses require transformation events to induce cell death/apoptosis
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Oncolytic Viruses
E.g. Parvovirus H1, Newcastle Disease Virus, (engineered) Adenovirus
Vähä-Koskela et al., 2007
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Molecular basis for selective permissiveness of cancer cells to oncolytic viruses
- Chromosomal instability
- Apoptosis resistance
- Higher levels of virus receptors (e.g. ICAM-1)
- Impaired anti-viral response (lack of critical IFN response)
- Adenovirus lacking E1B grows only in p53-minus cells
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Using viruses in conjunction with other forms of treatment
Nuesch/Rommelaere
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Viruses inducing cancer: lessons to be learnedSummary
Viruses transform cells by inhibiting apoptosisSV40
Viruses transform cells by inhibiting & inducing apoptosis
Adenovirus + others?
Oncolytic viruses “use” transforming events to kill cellsParvovirus H1 (NS1 protein)Newcastle disease virus
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Cancer and Apoptosis combinedAn historical Introduction
Apoptosis versus cancer
Viruses inducing Cancer: lessons to be learned
Proteins killing tumor cellsApoptin E4orf4 HAMLET MDA7 NS1 TRAIL
A brief preview to our workshop
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Transforming events are needed for proteins inducing tumor-specific apoptosis: Use of a
paradox?
DNA damage
Apoptosis
Arrest
Apoptosis
Survival
Pathway interference affecting cell transformation
Apoptin, E4orf4, HAMLET, NS1, MDA7, TRAIL
All seem to sense tumor-specific processes
Abrahams, unpublished
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Transformation events activate apoptin
ApoptosisNormal cells
+ LT/st
N localization
Apoptin + LTApoptin
a-108P
Phosphorylation
PengSV40 LT/st are transforming proteins
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E4orf4 affects directly tumor-related PP2A
PP2A
Lavoie
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Tumor factors encountered by HAMLET - MDA7 – TRAIL
TRAILMDA7
HAMLET
SvanborgRameshWalczak & Borst
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All Participants are invited to send in their contribution to the book
“Proteins Killing Tumour Cells”
Within the Research SignPost Series on
Cell Death and Disease
EditorsBackendorf – Borst - Noteborn – Tavassoli
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Organizers C Backendorf, J Borst
M Noteborn & M Tavassoli
Advisory Board membersJ Brouwer, M Green,
F Farzaneh & AJ van der Eb
WISH YOU A VERYFRUITFUL
LC-WORKSHOP
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References
Ali-Seyed et al., 2006, BMC Cancer 6, 54
Aylon & Oren, 2007, Cell 130, 597
Kooistra et al., Nov. 2007, MRMC, in press
Liu et al., 2007, Cancer Letters 250, 168
Reed, 2006, Nature Clinical Practice 3, 388
Sontag & Sontag, 2006, Cell. Mol. Life Sciences 63, 2979
Vähä-Koskela et al., 2007, Cancer Letters, 254, 178
White, 2006, Cell Death & Differentiation 13, 1371