Effects of ligand activation of peroxisome proliferator-activated receptor γ in human prostate cancer

Elisabetta Mueller, Matthew Smith, Pasha Sarraf, Todd Kroll, Anita Aiyer, Donald S. Kaufman, William Oh, George Demetri, William D. Figg, Xiao Ping Zhou, Charis Eng, Bruce M. Spiegelman*, Philip W. Kantoff

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

407 Scopus citations

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ 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 PPARγ 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 PPARγ 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 PPARγ may serve as a biological modifier in human prostate cancer and its therapeutic potential in this disease should be further investigated.

Original languageEnglish
Pages (from-to)10990-10995
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number20
DOIs
StatePublished - 26 Sep 2000
Externally publishedYes

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