Molecular Carcinogenesis 43: 198-205

He, G., S. Muga, P. Thuillier, R.A. Lubert, S.M. Fischer

What is PPAR-?

Peroxisome proliferator-activated receptor-gamma: member of the steroid nuclear hormone receptor superfamily

Three types of PPAR, encoded by separate genes: , each with own set of prefered ligands

PPAR- ligands: Thiazolidone class of drugs (ciglitazone, triglitazone,

rosiglitazone (Avandia- GSK, oral hypoglycemic drug)15-dPGJ2

Fatty acids

PPAR- has a role in adipocyte differentiation and fat metabolism.

Does PPAR- have a role in carcinogenesis?

Inhibit cancer: PPAR- activators can inhibit growth of breast cancer cell lines in vitro by increasing sensitization to apoptosis. Reported to Inhibit in vivo growth in xenogeneic system (nude mice) and various in vivo cancer models.

Promote cancer: Two reports that thiazolidone drugs promote colon cancer in animal models.

Lisa’s data (J. Nutrition, 2005) is inconclusive: in vitro data indicates that PPAR- inhibits tumor growth. In vivo data is another story- leans towards being pro-tumor (still a lot of questions).

What about skin cancer?

PPAR- in skin cancer

PPAR- +/- mice are more susceptible to DMBA-induced skin papilloma development compared to PPAR-g +/+ (wt) mice (Nicol et al, Carcinogenesis, 2004).

In human skin, PPAR- associated with keratinocyte differentiation: supra-basal cells only (Westergaard et al, JID, 2001).

In vitro, PPAR-g ligands inhibit growth of cultured mouse keratinocytes. However, PPAR- protein was not detected in the keratinocytes (He et al, JID,2004).

UV 3x/week for 15 weeks(90mJ/cm2 start, increase 10% weekly to 175mJ/cm2)

Mice randomized to rosi+ or rosi- diet weeks 15-29(rosi 200ppm- very high compared to what Lisa uses- 12mg/kg)

Tu

mo

rs/m

ou

se%

mic

e w

ith

tu

mo

rs

No difference

Effect of Dietary Rosiglitazone on UV Skin Carcinogenesis

Effect of Topical Troglitazone on UV carcinogenesis

Tu

mo

rs/m

ou

se%

mic

e w

ith

tu

mo

rs

UV 3x/week then topical treatment with 100g troglitazone or acetone

No significant effect

Effect of Dietary Rosi on DMBA/TPA skin carcinogenesis

Tu

mo

rs/m

ou

se%

mic

e w

ith

tu

mo

rs

FVB/n mice, shaved, 100g DMBA, at 2 weeks, 3x/week treatment with 2.5g TPA

Mice randomized to rosi+ or rosi- diet weeks 2-17(rosi 300ppm- very high compared to what Lisa uses- 12mg/kg)

No significant effect

2000ppm troglitazone for 1 week

TPA or vehicle, then inject with BrdU

Inhibits control proliferation, but not TPA-induced proliferation

Effect of dietary Troglitazone on BrdU labeling (epidermal proliferation)

PPAR-mRNA(Northern blot)

F= fatP=primary keratinocyteE= epidermisW= whole skinT= tumor

FVB/N

FVB/N

SKH

UV

FVB/n20X

FVB/n40X

UVSkin tumor

FVB/n40X

FVB/n (40X)From BrdU expt

UV

FVB/n20X

FVB/n40X

UVSkin tumor

UV skin tumor

No section of normal SKH skin

Conclusions from this paper

PPAR- ligands did not significantly alter skin tumor development when used at 200-2000ppm

Lisa uses dietary Rosiglitazone and Fish oil to activate PPAR-

In breast cancer: Fish oil protective, PPAR- does not appear to be protective (still trying to figure out what’s going on

model specific (Her-2/neu Tg mice)dose of Rosi (12mg/kg vs 200ppm)

In human studies, TGF- induces PPAP- and inhibits CTL restimulation. Further, PPAR- ligand ciglitazone induces PPAR- and alters APC function so that CTL restimulation is inhibited (Kelly’s expts)

What about fish oil and Rosi in UV inflammation and carcinogenesis?

Stimulation Index, 4 week diet

1.95

2

2.05

2.1

2.15

2.2

2.25

2.3

2.35

chow fish oil corn oil

Sti

mu

lati

on

In

dex

Avg food consumption/mouse/group

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

chow fish corn fish+rosi corn+rosi

avera

ge f

ood

(g

)

6 week diet, weights

15

17

19

21

23

25

27

29

31

33

35

6.24.05 7.1.05 7.8.05 7.15.05 7.22.05 7.29.05

dates

ave

rag

e w

eig

ht

(g)

chow fish oil corn oil fish oil+rosi corn oil + rosi

fish

Fish+ rosi

Skin Thickness 6wk-48hr

0

0.2

0.4

0.6

0.8

1

1.2

1.4

chow fish oil corn oil fish+rosi corn+rosi

Skin

th

ickn

ess (

mm

)

* **

**

PPAR-

Fatty acids(LA,DHA,EPA)

Breast cancer

eicosanoidsFatty acidderivatives

Thiazolidinediones(rosiglitazone)

HER-2/neu+

Estrogen RProgesterone R

RXR

RAR

Fatmetabolism

Adipocytedifferentiation

Cell proliferation,tumorigenesis