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Experimental Therapeutics |
in Human Prostate Cancer1
Division of Hematology/Oncology [J-i. H., T. I., H. P. K.] and Department of Surgery [S. H.], Cedars-Sinai Medical Center, University of California–Los Angeles School of Medicine, Los Angeles, California 90048; Biological Chemistry and Molecular Biology Institute, University of California, Los Angeles, California 90095 [M. C.]; and Department of Hematology, Showa University School of Medicine, Tokyo 142, Japan [S. T.]
The peroxisome proliferator-activated receptor gamma (PPAR
) is a
member of the nuclear receptor superfamily. Recent studies found that
ligand-activated PPAR regulated differentiation and clonal growth of
several types of cancer cells, including prostate cancer, suggesting
that PPAR could be a tumor suppressor. Troglitazone was a widely
used antidiabetic drug that activates PPAR. Recently, we reported
that this agent had antiprostate cancer effects in vitro
and in vivo. In this study, we administered troglitazone
for over 1.5 years to an individual with occult recurrent prostate
cancer. Using the prostate-specific antigen (PSA) levels as a surrogate
marker of the disease, the oral administration of troglitazone
(600–800 mg/day) reduced the increase velocity of PSA levels,
suggesting clinical efficacy of troglitazone in prostate cancer. PSA
promoter/enhancer reporter assays showed that the PPAR ligands
troglitazone (10-5 M), pioglitazone (10-5 M),
or 15-deoxy-
12,14-prostaglandin J2 (10-5 M)
down-regulated androgen-stimulated reporter gene activity in LNCaP
cells, a prostate cancer cell line. The PSA promoter contains androgen
receptor response elements (AREs). Reporter gene studies showed that
troglitazone inhibited androgen activation of the AREs in the PSA
regulatory region. Consistent with inhibition of gene expression, 2
days of incubation of LNCaP with troglitazone dramatically suppressed
PSA protein expression without suppressing AR expression, suggesting
that troglitazone inhibited ARE activation by a mechanism other than
down-regulation of expression of the AR. Taken together, ligands of
PPAR may be a useful therapeutic approach for the treatment of
prostate cancer and may be acting, in part, by inhibiting
transactivation of androgen-responsive genes.
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