The Role Of Androgen Receptor In The Atophagy Induced By Proteasome Inhibitor

Prostate cancer has always been causing much trouble to the health of men inEurope and America, besides, the incidence of prostate cancer has a rising trend yearby year in China. Conventional androgen-ablation therapy can only delay thedevelopment of prostate cancer in a short period, but most patients at last relapses toa hormone-refractory prostate cancer to which, at present, there is no effectivetherapy. So research on therapy targeting androgen receptor may lend a hand toprostate cancer therapy.Proteasome inhibitor is a novel anti-tumor drug, which targets the mamalianproteasome, and it can cause proliferation inhibition and apoptosis to many kinds ofhematologic tumor. Proteasome play an important role in enzyme activity controland protein synthesis quality control. Compared to normal cells, cancers have higherlevels of metabolism and proliferation which demands higher level of proteasomeactivity. And this is one of the mechanisms why proteasome inhibitor canspecifically kill tumor cells. However, proteasome inhibitor has limited effect tosolid tumor cells, such as prostate cancer cells, besides, people found that it caninduce autophagy in many kinds of cancer cells, which may be one of themechanisms to tumor cell drug resistance.Androgen ablation leads to inducion of autophagy in prostate cancer, whichmay be one of the cause to hormone refractory prostate cancer. The coincidenc ofchange in androgen receptor midiated signaling pathway and induction of autophagysuggest a potential regulatory relationship between them. In this project, we firstconformed that proteasome inhibitor bortezomib could induce autophagy in prostatecancer LNCaP cells through TEM, fluorescent microscope，western blotting andRT-qPCR. Then we found that decreased androgen receptor lead to increased basallevel autophagy in LNCaP cells. Next we found that induction of autophagy by BTZis more mild in AR positive cell lines compared with those AR negtive cell lines.Then we found that exogenous androgen receptor could also inhibit autophagyinduced by bortezomib. At last, we found that autophagy induced by proteasomeinhibitor is to some extent protective for prostate cancer cell, as combination of BTZand autophagy inhibitor lead to more decrease in cell viability. In sum, throughseries of experiment, we demenstrated that AR could inhibit autophagy induced byproteasome inhibitor in prostate cancer, which provide valuable experimentevidence to research on AR-targeted prostate cancer therapy.