Elucidation of scandenolone as anti-cancer activity through impairment of the metabolic and signaling vulnerabilities in prostate cancer

Prostate cancer (PCa) is the most prevalent men’s cancer in America and Western countries. No effective therapies are currently available for PCa aggressiveness, including castration-resistant progression (CRPC). This study aims at evaluation of the prospective efficacy and the molecular mechanism of scandenolone (SCA), a natural isoflavone, in PCa progression. SCA suppressed cell viability and progression and induced apoptosis in PCa cells. SCA inhibited the expression of lipogenesis and cholesterogenesis related key genes. Through inhibition of these metabolic genes, SCA decreased the levels of fatty acids, lipid droplets and cholesterols in PCa cells. Moreover, SCA enhanced the expression of antioxidant factors, including Nrf2, HO-1, catalase and SOD-1, and reduced the ROS levels in PCa cells. Substantially, SCA displayed the potential efficacy on CRPC tumors. This paper offers a new insight into the underlying molecular basis of SCA in PCa cells. By coordinated impairment of the metabolic and signaling vulnerabilities, including lipogenesis, cholesterogenesis, ROS and the AR/PSA axis, SCA could be applied as a novel and promising remedy to cure malignant PCa. SCA inhibited cell growth, migration and invasion, and induced caspase-dependent apoptosis through blockade of the metabolic and signaling vulnerabilities, including lipogenesis (inhibition of SREBP-1 and FASN), cholesterogenesis (inhibition of SREBP-2 and HMGCR), ROS (activation of Nrf2, HO-1, catalase and SOD) and the AR/PSA axis in PCa cells. [Display omitted] •Three key transcriptional factors mediating the metabolic and signaling vulnerabilities (lipogenesis, cholesterogenesis and ROS) were identified leading to prostate cancer (PCa) progression.•Scandenolone (SCA), a natural isoflavone product, exhibited a potential nti-cancer activity on suppression of cell viability and progression, and activation of programmed cell death in PCa cells in vitro and in vivo.•SCA co-impaired lipogenesis, cholesterogenesis and ROS in PCa.•SCA could be applied as a novel and promising drug to cure malignant PCa.