Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor that plays a key role in the differentiation of adipocytes. Activation of this receptor in liposarcomas and breast and colon cancer cells also induces cell growth inhibition and differentiation. In the present study, we show that PPARgamma is expressed in human prostate adenocarcinomas and cell lines derived from these tumors. Activation of this receptor with specific ligands exerts an inhibitory effect on the growth of prostate cancer cell lines. Further, we show that prostate cancer and cell lines do not have intragenic mutations in the PPARgamma gene, although 40% of the informative tumors have hemizygous deletions of this gene. Based on our preclinical data, we conducted a phase II clinical study in patients with advanced prostate cancer using troglitazone, a PPARgamma ligand used for the treatment of type 2 diabetes. Forty-one men with histologically confirmed prostate cancer and no symptomatic metastatic disease were treated orally with troglitazone. An unexpectedly high incidence of prolonged stabilization of prostate-specific antigen was seen in patients treated with troglitazone. In addition, one patient had a dramatic decrease in serum prostate-specific antigen to nearly undetectable levels. These data suggest that PPARgamma may serve as a biological modifier in human prostate cancer and its therapeutic potential in this disease should be further investigated.
Mueller
E
E
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Smith
M
M
Sarraf
P
P
Kroll
T
T
Aiyer
A
A
Kaufman
D S
DS
Oh
W
W
Demetri
G
G
Figg
W D
WD
Zhou
X P
XP
Eng
C
C
Spiegelman
B M
BM
Kantoff
P W
PW
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division; D002839:Chromans / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002839:Chromans; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077288:Troglitazone