Ligands for peroxisome proliferator-activated receptor gamma have potent antitumor effect against human renal cell carcinoma.
OBJECTIVE
To examine whether peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in human renal cell carcinoma (RCC) cells, and whether activation of PPARgamma by its ligands can have multiple antitumor effects on human RCC cells in vitro.


METHODS
We examined the expression of PPARgamma in four human RCC cell lines by reverse transcriptase-polymerase chain reaction and immunocytochemical staining. The effects of two PPARgamma ligands, pioglitazone and 15-deoxy-Delta12,14-prostaglandin J2, on cell proliferation were investigated by 3-[4,5-dimethylthiazol-2-thiazoly]-2,5-diphenyltetrazolium bromide assay. The induction of apoptosis by the ligands was examined using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling method and Annexin V assay. Furthermore, we investigated whether these ligands suppressed the production of angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor, by enzyme-linked immunosorbent assay.


RESULTS
PPARgamma and retinoid X receptor, which forms a heterodimer with PPARgamma, were expressed in all RCC cell lines. In addition, immunocytochemical studies showed expression of PPARgamma protein in the RCC cells. PPARgamma ligands inhibited the cell growth in all cells in a dose-dependent manner. These ligands also induced apoptosis. Furthermore, secretion of both vascular endothelial growth factor and basic fibroblast growth factor was inhibited by these ligands in a dose-dependent and time-dependent manner.


CONCLUSIONS
Ligands for PPARgamma have multiple antitumor effects in human RCC cells in vitro. Activation of the PPARgamma pathway may be a new strategy for treatment of patients with RCC.
Yuan
Jinyang
J
Department of Urology, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo, Japan.
Takahashi
Atsushi
A
Masumori
Naoya
N
Uchida
Kohsuke
K
Hisasue
Shin-Ichi
S
Kitamura
Hiroshi
H
Itoh
Naoki
N
Tsukamoto
Taiji
T
D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
C477819:15-deoxyprostaglandin J2; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; D045162:Thiazolidinediones; D015230:Prostaglandin D2; D000077205:Pioglitazone