Therapeutic interference of SREBP-mediated lipid metabolism by E-Xanthohumol attenuates prostate cancer progression.

Aberrant lipid metabolism, driven by two key transcriptional regulators (SREBP-1 and SREBP-2) and their downstream enzymes, contributes to prostate cancer (PCa) development and progression to lethal castration-resistant PCa (CRPC). Targeting the SREBP-1 and SREBP-2 networks offer a promising therapeutic strategy by simultaneous inhibition of the multiple lipogenic pathways and the androgen receptor (AR). A naturally occurring prenylated chalcone, (E)-Xanthohumol (EXN), has emerged as a potent modulator of cellular metabolism, exhibiting the antioxidant properties and neuroprotective effects. However, the mechanistic impact of EXN on the dysregulated lipogenic pathways in PCa cells remains unknown. In this study, we aimed at revealing the molecular basis and determining the efficacy of EXN on PCa aggressiveness in vitro and in vivo. EXN significantly suppressed growth, migration and invasion in both androgen-dependent and CRPC PCa cells. Furthermore, EXN induced intrinsic caspase-dependent apoptosis in PCa cells. Remarkably, EXN downregulated expression of SREBP-1, SREBP-2 and their downstream regulated genes, including Fatty Acid Synthase (FASN) and β-Hydroxy β-methylglutaryl-CoA reductase (HMGCR), as well as AR. Lipidomic analysis demonstrated a significant decrease of triglycerides and cholesterol esters following EXN treatment in PCa cells. These overall effects were translated into attenuation of CRPC tumor growth in nude mice. In summary, our findings highlight EXN is a novel and potential anti-PCa agent via targeting dysregulated lipid metabolism mediated by SREBP. EXN would be able to overcome the shortcomings of current hormonal therapy against PCa emphasizing its clinical relevance.