Abstract

Vitamin A (retinol) and its related metabolites such as retinoic acid (RA), called retinoids, act by regulating cell proliferation and differentiation and are used to treat patients with urologic cancers. We analyzed retinoid signaling and metabolism in the TRAMP (Transgenic Adenocarcinoma Mouse Prostate) model. We detected increased retinol and retinyl esters in prostates pooled from 24-36 week old TRAMP transgenic positive mice compared to nontransgenic littermates by HPLC analysis. Transcript levels of ALDH1A1 were decreased in the ventral and lateral prostate lobes from TRAMP mice compared to age-matched nontransgenic mice at 18-36 weeks by quantitative RT-PCR. ALDH1A2 mRNA levels in the dorsal (36 week) and anterior (24 week) lobes of TRAMP mice were lower than in age-matched nontransgenic mice. Lower RARβ₂ mRNA levels were observed in dorsal prostates of 36 week TRAMP mice relative to nontransgenic mice. ALDH1A2 protein levels were reduced in all prostate lobes of TRAMP mice compared to nontransgenic mice by immunohistochemistry. We also detected much lower ALDH1A2 protein levels in all human prostate cancer specimens stained relative to adjacent benign prostate tissue. Our data indicate that this reduction in ALDH1A2 protein is an early event in human prostate cancer.

The efficacy of combination therapy involving RA and the HDAC inhibitor trichostatin A (TSA) was tested using two RA-resistant human renal cell carcinoma (RCC) lines, SK-RC-39 and SK-RC-45. A xenograft tumor model (SK-RC-39) was utilized to investigate the efficacy of a liposome-encapsulated, intravenous form of RA (ATRA-IV) plus TSA combination therapy. Enhanced growth inhibition of RCC cell lines and of tumor growth in the xenograft model was observed with the combination of RA plus TSA. Reactivation of RARβ₂ mRNA expression was observed in SK-RC-39 and SK-RC-45 cells treated with TSA alone, or TSA plus RA. Analysis of apoptosis was performed on SK-RC-39 cells treated with these combinations. A partial G0/G1 arrest and increased apoptosis were observed in SKRC-39 cells treated with RA and TSA. The combination of RA and TSA elicits an additive inhibition of cell proliferation in RCC cell lines. These results indicate that RA and HDAC inhibitor therapies should be further explored for RCC treatment.