Introduction: There is a need for seeking effective treatments for CRPC, because its emergence following ADT is a major clinical problem. In the present study, we investigated chemopreventive and chemotherapeutic potential of luteolin, which is a flavonoid, on prostate cancer including CRPC.
Methods: Firstly, six-week-old male transgenic rats for adenocarcinoma of prostate (TRAP) were divided into three groups and fed the following for 8 weeks: basal diet, diet containing luteolin. Prostate tissues were collected for histopathological, gene, and protein expression analysis. Next, we also focused on androgen receptor splice variants (including AR-V7), which contributes to cell proliferation and therapeutic resistance of CRPC, and microarray analysis identified miR-8080, which contains a possible target sequence for AR-V7 3’UTR, as an up-regulated gene following luteolin treatment. Subsequently, in vitro analysis using iRNA and overexpression system as to miR-8080 was established, and the effect of luteolin on cell proliferation and apoptosis in PCai1 and 22Rv1 cells was analyzed. Thirdly, PCai cells and 22Rv1 cells were subcutaneously implanted in castrated and non-castrated nude mice, and in vivo tumor growth after luteolin and enzalutamide treatment was analyzed.
Results: Luteolin inhibited the progression of rat prostate carcinogenesis by induction of apoptosis in the TRAP model. Luteolin decreased cell proliferation in a dose-dependent manner and induced apoptosis with activation of caspase in both rat (PCai1) and human (22Rv1) CRPC cells. Dietary luteolin also suppressed tumor growth via induction of apoptosis and inhibition of angiogenesis in PCai1 and 22Rv1 xenograft models. Luteolin dramatically suppressed AR-V7 protein expression in 22Rv1 cells in vitro and ex vivo. miR-8080 transduction decreased AR-Vs and induction of apoptosis in 22Rv1. Furthermore, miR-8080 knock-down abrogated the luteolin-dependent reduction of AR-V7 protein and cell growth. Induction of miR-8080 following luteolin intake enhanced the chemotherapeutic effect of enzalutamide in 22Rv1 xenografts.
Conclusions: These results indicate luteolin inhibits CRPC growth downregulating AR-Vs via miR-8080, and that luteolin or miR-8080 mimetics may be promising chemotherapeutic agents for CRPC treatment. Source of
Funding: Grant-Aid from the Ministry of Education, Culture, Sports Science and Technology of Japan [17K11155]