Investigation of the Signal Pathways Involved in Resistin Modulation of Human Prostate Cancer Cell Growth

Prostate cancer (PCa) is the most common cancer of the reproductive system in elderly men.Recent studies indicated that a higher risk of developing PCa is associated with obesity andadipokines. Our preliminary data showed that resistin, a cysteine-rich hormone that was firstisolated from adipose tissues to link obesity to type II diabetes, was found to stimulate the growthof androgen-independent PC-3 PCa cells but not androgen-dependent LNCaP PCa cells. Also,resistin stimulated the growth of PC-3 cells through the PI3K/AKT and ERK MAPK pathways. Inaddition, resistin induced increases in levels of suppressor of cytokine signaling (SOCS)-1, -2, -3,-4, -5, and -6, but not SOCS-7 or cytokine-inducible SH2-containing protein-1 (CIS-1), mRNAs inPC-3 cells. The specific inhibitors of PI3K/AKT blocked the resistin-stimulated expressions ofthese SOCS mRNAs, and SOCS-5 gene knockdown reduced the stimulatory effect of resistin on thegrowth of PC-3 cells. Interestingly, LNCaP cells exhibited the less or silent resistin, SOCS-1 and -3expressions, and PCa tissue tended to express greater levels of resistin, SOCS-3, -4 and -5 mRNAsthan normal prostate tissue from commercial tissue cDNA arrays. Significant positive correlationsof resistin with SOCS-4 and -5 were observed. Despite the findings that resistin can regulate thegrowth and certain SOCS expressions in PCa cells, it is still unknown whether resistin receptor,so-called toll-like receptor (TLR)-4, mediates the effect of resistin on PCa and whether the SOCSsand their upstream JAK/STAT are responsible for transducing resistin growth signal on PCa cells.Thus, the main hypothesis arises that resistin may regulate the growth of androgen-independent PCacells through modulations of particular MAPK, JAK, STAT, SOCS, and TLR members.To test the hypothesis and to fully understand the impacts of resistin on human PCa, theinitial goals of our 3-year proposal are designed to investigate the signal pathways involved inresistin modulations of androgen-independent PCa cell growth. Aims I and II are to study theMAPK signaling pathway and JAK/STAT signaling pathway involved in resistin modulationof PCa cell growth, respectively. Aim III is to study the upstream and downstream signalelements of PI3K/AKT in the resistin regulation of PCa cell growth. Aims IV and V are tostudy the SOCS signaling pathway and TLR signaling pathway involved in resistin regulationof human PCa cell growth, respectively. Aim VI is to study the correlation of resistin withTLR-4 and SOCS molecules in PCa from commercial human PCa tissue arrays, and Aim VIIis to study the in vivo effects of resistin on human PCa growth in PCa cell-xenografted mice.We anticipate elucidating signaling mechanisms (e.g., TLR-4/JAK/STAT/SOCS) that underliethe action of resistin on the growth of human PCa cells. This project also leads us to a betterunderstanding of how resistin acts on PCa cells in vitro and in vivo. As PCa is the most commoncancer of the reproductive system in elderly men and associates with obesity, our discoveries fromthe actions of resistin on PCa cells may provide the fundamental basis for understandingobesity-related PCa. Understanding what signaling elements transduce distinct resistin signalsbetween androgen-dependent and androgen-independent prostate cancer cells may provide theintellectual merits for academic and patent development plans that help evaluate a clinical trial onhormonal therapy for PCa. We gain new insights into resistin’s role in the reproductive disease.