Peroxisome Proliferator-Activated Receptor γ Induces Pancreatic Cancer Cell Apoptosis

Abstract Peroxisome proliferator-activated receptor gamma (PPAR-γ) decreases the growth of certain cancer cells. In the present study, we found that six different human pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-2, HPAF-II, MIA PaCa-2, and PANC-1) expressed PPAR-γ m-RNA and synthesized the protein. The endogenous and exogenous PPAR-γ ligands 15-deoxy-d12,14-prostaglandin J 2 (15-PGJ 2 ) and ciglitazone decreased cell number, cell viability, and increased floating/attached ratio, in a time- and dose-dependent fashion. 15-PGJ 2 increased intracellular nucleosome concentration after 6 h, but did not increase caspase-3 activity even after 96 h. Combined treatment with both 15-PGJ 2 and the caspase-3 inhibitor DEVD-CHO had no effect on cell viability, but the general caspase inhibitor ZVAD-FMK reduced 15-PGJ 2 -induced apoptosis. We concluded that the six human pancreatic cancer cells tested all expressed PPAR-γ receptor, and treatment with PPAR-γ agonists decreased cell viability and growth in a time- and dose-dependent manner. These effects were partially mediated by induction of caspase-3 independent apoptosis.

[1]  T. Terada,et al.  PPARgamma ligand (thiazolidinedione) induces growth arrest and differentiation markers of human pancreatic cancer cells. , 2000, International journal of oncology.

[2]  B. Spiegelman,et al.  Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[3]  E. Brown,et al.  Expression of peroxisome proliferator‐activated receptors (PPARS) in human astrocytic cells: PPARγ agonists as inducers of apoptosis , 2000 .

[4]  G. Atsumi,et al.  15-deoxy-Δ12,14PGJ2 induces diverse biological responses via PPARγ activation in cancer cells , 2000 .

[5]  C. Paraskeva,et al.  Apoptosis induction and cyclooxygenase‐2 regulation in human colorectal adenoma and carcinoma cell lines by the cyclooxygenase‐2‐selective non‐steroidal anti‐inflammatory drug NS‐398 , 2000, International journal of cancer.

[6]  M. Kondo,et al.  Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-gamma agonists through induction of apoptosis. , 2000, Biochemical and biophysical research communications.

[7]  Y. Matsuzawa,et al.  PPARgamma inhibits the expression of c-MET in human gastric cancer cells through the suppression of Ets. , 1999, Biochemical and biophysical research communications.

[8]  V. Seewaldt,et al.  Peroxisome proliferator-activated receptor gamma activation in human breast cancer. , 1999, International journal of oncology.

[9]  M. Willingham,et al.  Influence of J series prostaglandins on apoptosis and tumorigenesis of breast cancer cells. , 1999, Carcinogenesis.

[10]  R. Breyer,et al.  Expression of Peroxisome Proferator-Activated Receptor γ (PPARγ) in Human Transitional Bladder Cancer and its Role in Inducing Cell Death , 1999 .

[11]  M. Mitchell,et al.  15-Deoxy-Delta(12,14)-prostaglandin J(2), a ligand for peroxisome proliferator-activated receptor-gamma, induces apoptosis in JEG3 choriocarcinoma cells. , 1999, Biochemical and biophysical research communications.

[12]  T. Hla,et al.  Endothelial Cell Apoptosis Induced by the Peroxisome Proliferator-activated Receptor (PPAR) Ligand 15-Deoxy-Δ12,14-prostaglandin J2 * , 1999, The Journal of Biological Chemistry.

[13]  B. Spiegelman,et al.  Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[14]  J Auwerx,et al.  Mechanism of action of fibrates on lipid and lipoprotein metabolism. , 1998, Circulation.

[15]  T. Willson,et al.  The nuclear receptor PPARγ - Bigger than fat , 1998 .

[16]  J. Auwerx,et al.  Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice , 1998, Nature Medicine.

[17]  J. G. Alvarez,et al.  Activators of the nuclear receptor PPARγ enhance colon polyp formation , 1998, Nature Medicine.

[18]  H P Koeffler,et al.  Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. , 1998, Cancer research.

[19]  H P Koeffler,et al.  Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[20]  B. Spiegelman.  PPARγ in Monocytes: Less Pain, Any Gain? , 1998, Cell.

[21]  B. Spiegelman,et al.  Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  B. Spiegelman,et al.  Adipogenesis and Obesity: Rounding Out the Big Picture , 1996, Cell.

[23]  J. Lehmann,et al.  A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation , 1995, Cell.

[24]  B. Spiegelman,et al.  15-Deoxy-Δ 12,14-Prostaglandin J 2 is a ligand for the adipocyte determination factor PPARγ , 1995, Cell.

[25]  Eric F. Johnson,et al.  Novel Sequence Determinants in Peroxisome Proliferator Signaling (*) , 1995, The Journal of Biological Chemistry.

[26]  K. Umesono,et al.  Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling , 1992, Nature.

[27]  I. Issemann,et al.  Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators , 1990, Nature.

[28]  J. Reddy,et al.  Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens , 1980, Nature.

[29]  E. Lock,et al.  Biochemical mechanisms of induction of hepatic peroxisome proliferation. , 1989, Annual review of pharmacology and toxicology.