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Molecular Carcinogenesis 43: 198-205

He, G., S. Muga, P. Thuillier, R.A. Lubert, S.M. Fischer. Molecular Carcinogenesis 43: 198-205. What is PPAR- g ?. Peroxisome proliferator-activated receptor-gamma: member of the steroid nuclear hormone receptor superfamily

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Molecular Carcinogenesis 43: 198-205

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  1. He, G., S. Muga, P. Thuillier, R.A. Lubert, S.M. Fischer Molecular Carcinogenesis 43: 198-205

  2. What is PPAR-g? Peroxisome proliferator-activated receptor-gamma: member of the steroid nuclear hormone receptor superfamily Three types of PPAR, encoded by separate genes: a, b, g, each with own set of prefered ligands PPAR-g ligands: Thiazolidone class of drugs (ciglitazone, triglitazone, rosiglitazone (Avandia- GSK, oral hypoglycemic drug) 15-dPGJ2 Fatty acids PPAR-g has a role in adipocyte differentiation and fat metabolism.

  3. Does PPAR-g have a role in carcinogenesis? Inhibit cancer: PPAR-g 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-g inhibits tumor growth. In vivo data is another story- leans towards being pro-tumor (still a lot of questions). What about skin cancer?

  4. PPAR-g in skin cancer PPAR-g +/- 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-g 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-g protein was not detected in the keratinocytes (He et al, JID,2004).

  5. Effect of Dietary Rosiglitazone on UV Skin Carcinogenesis Tumors/mouse 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) % mice with tumors No difference

  6. Effect of Topical Troglitazone on UV carcinogenesis UV 3x/week then topical treatment with 100mg troglitazone or acetone Tumors/mouse % mice with tumors No significant effect

  7. Effect of Dietary Rosi on DMBA/TPA skin carcinogenesis Tumors/mouse FVB/n mice, shaved, 100mg DMBA, at 2 weeks, 3x/week treatment with 2.5mg TPA Mice randomized to rosi+ or rosi- diet weeks 2-17 (rosi 300ppm- very high compared to what Lisa uses- 12mg/kg) % mice with tumors No significant effect

  8. Effect of dietary Troglitazone on BrdU labeling (epidermal proliferation) 2000ppm troglitazone for 1 week TPA or vehicle, then inject with BrdU Inhibits control proliferation, but not TPA-induced proliferation

  9. PPAR-g mRNA (Northern blot) FVB/N F= fat P=primary keratinocyte E= epidermis W= whole skin T= tumor SKH FVB/N

  10. FVB/n 20X FVB/n 40X FVB/n (40X) From BrdU expt FVB/n 40X UV UV Skin tumor

  11. FVB/n 20X FVB/n 40X UV UV skin tumor No section of normal SKH skin UV Skin tumor

  12. Conclusions from this paper PPAR-g ligands did not significantly alter skin tumor development when used at 200-2000ppm Lisa uses dietary Rosiglitazone and Fish oil to activate PPAR-g In breast cancer: Fish oil protective, PPAR-g 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-b induces PPAP-g and inhibits CTL restimulation. Further, PPAR-g ligand ciglitazone induces PPAR-g and alters APC function so that CTL restimulation is inhibited (Kelly’s expts) What about fish oil and Rosi in UV inflammation and carcinogenesis?

  13. fish Fish+ rosi

  14. * * * * *

  15. Thiazolidinediones (rosiglitazone) eicosanoids Fatty acids (LA,DHA,EPA) Fatty acid derivatives RXR Breast cancer PPAR- HER-2/neu+ RAR Estrogen R Progesterone R Cell proliferation, tumorigenesis Adipocyte differentiation Fat metabolism

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