GL-V9 inhibits the activation of AR-AKT-HK2 signaling networks and induces prostate cancer cell apoptosis through mitochondria-mediated mechanism

Prostate cancer (PCa) is a serious health concern for men due to its high incidence and mortality rate. The first therapy typically adopted is androgen deprivation therapy (ADT). However, patient response to ADT varies, and 20–30% of PCa cases develop into castration-resistant prostate cancer (CRPC). This article investigates the anti-PCa effect of a drug candidate named GL-V9 and highlights the significant mechanism involving the AKT-hexokinase II (HKII) pathway. In both androgen receptor (AR)-expressing 22RV1 cells and AR-negative PC3 cells, GL-V9 suppressed phosphorylated AKT and mitochondrial location of HKII. This led to glycolytic inhibition and mitochondrial pathway-mediated apoptosis. Additionally, GL-V9 inhibited AR activity in 22RV1 cells and disrupted the feedback activation of AKT signaling in condition of AR inhibition. This disruption greatly increased the anti-PCa efficacy of the AR antagonist bicalutamide. In conclusion, we present a novel anti-PCa candidate and combination drug strategies to combat CRPC by intervening in the AR-AKT-HKII signaling network. [Display omitted] •GL-V9 induces mitochondria-mediated apoptosis in AR-positive and AR-negative PCa cells•GL-V9 suppresses p-AKT, mitochondrial location of HKII and activation of AR signal•GL-V9 disrupts feedback activation of AKT signaling in condition of AR inhibition•GL-V9 exhibits a synergistic effect when combined with AR inhibitors in PCa treatment Classification Description: Molecular biology; Cell biology; Cancer