Recruitment of miR-8080 by luteolin inhibits androgen receptor splice variant 7 expression in castration-resistant prostate cancer

Abstract

A need exists for seeking effective treatments for castration-resistant prostate cancer (CRPC) in response to its emergence following androgen deprivation therapy as a major clinical problem. In the present study, we investigated the chemopreventive and chemotherapeutic potential of luteolin, a flavonoid with antioxidative properties, on prostate cancer, including CRPC. Luteolin inhibited the progression of rat prostate carcinogenesis by induction of apoptosis in a transgenic rat for adenocarcinoma of prostate (TRAP) model. Luteolin decreased cell proliferation in a dose-dependent manner and induced apoptosis with the activation of caspases 3 and 7 in both rat (PCai1, established from a TRAP prostate tumor) and human (22Rv1) CRPC cells. Dietary luteolin also suppressed tumor growth via an increase in apoptosis and inhibition of angiogenesis in PCai1 and 22Rv1 xenografts implanted in castrated nude mice. We also focused on androgen receptor splice variant 7 (AR-V7), which contributes to cell proliferation and therapeutic resistance in CRPC. Luteolin dramatically suppressed AR-V7 protein expression in 22Rv1 cells in vitro and ex vivo. Microarray analysis identified MiR-8080, which contains a possible target sequence for AR-V7 3′-UTR, as a gene upregulated by luteolin. MiR-8080 transfection decreased the AR-V7 expression level and the induction of apoptosis in 22Rv1 cells. Furthermore, miR-8080 knockdown canceled luteolin decreasing AR-V7 and the cell growth of 22Rv1. MiR-8080 induced by luteolin intake enhanced the therapeutic effect of enzalutamide on 22Rv1 xenografts under castration conditions. These results indicate luteolin inhibits CRPC by AR-V7 suppression through miR-8080, highlighting luteolin and miR-8080 as promising therapeutic agents for this disease.

Hexane Insoluble Fraction from Purple Rice Extract Retards Carcinogenesis and Castration-Resistant Cancer Growth of Prostate Through Suppression of Androgen Receptor Mediated Cell Proliferation and Metabolism

“…PRE-HIF reduced Ki-67 index by more than 20% (from 79.7 ± 16.8% to 54.3 ± 18.8%) in lateral prostate of TRAP model, while it did not alter the apoptotic index (control: 3.8 ± 1.0%, 1% PRE-HIF: 3.3 ± 1.4%, respectively). In accordance with previous studies, TUNEL indices were increased by around 5%-6%, at least less than 10% with induction of apoptosis by test chemicals in prostate cancer tissue [13,17]. This indicates that a strong anti-proliferative effect may provide chemopreventive or chemotherapeutic effects without induction of apoptosis.…”

“…At 15 weeks of age, non-invasive adenocarcinomas developed within prostates under hormone-dependent conditions [11]. Consequently, the TRAP model has been widely used for exploring the chemopreventive effect of several compounds against prostate carcinogenesis [12][13][14][15][16][17]. In addition to an androgen-sensitive phase, we evaluated the effect of PRE-HIF on androgen-insensitive prostate cancer using PCai1 cells.…”

Luteolin suppresses bladder cancer growth via regulation of mechanistic target of rapamycin pathway

“…We further analyzed any change in squamous differentiation, which relates to worse recurrence and progression rates with luteolin, because we previously found that the oxidative stress‐regulated gene glutathione peroxidase 2 ( GPX2 ) was upregulated in several carcinomas, including UC, and promoted squamous differentiation . Moreover, we recently found that luteolin downregulated GPX2 in the rat prostate tumor and in a human prostate cancer cell line . The frequency of squamous differentiation in the tumors was significantly decreased in the luteolin‐treated groups ( P < 0.05; Figure E,).…”

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

“…Luteolin induced apoptosis and inhibited the progression of rat prostate carcinogenesis in a transgenic rat for adenocarcinoma of prostate (TRAP) model in addition to a xenograft prostate cancer model where angiogenesis was also inhibited. In another human and rat cell model of prostate cancer, luteolin induced apoptosis by activation of caspases-3 and 7 [387]. Additionally, migration and tumorigenesis were inhibited, and apoptosis was induced in a glioblastoma model.…”

“…Inflicted double-stranded DNA breaks and prevented nonhomologous end joining [385]. Induced apoptosis [374,375,382,[386][387][388]. Reduced migration and invasion [378,379,[388][389][390].…”