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Therapeutic interference of SREBP-mediated lipid metabolism by E-Xanthohumol attenuates prostate cancer progression
Jonathan Viehoever1, Naveen Surya Velmani2, Vignesh Basavaraj2
1International Master's Program of Biomedical Sciences, School of Medicine, China Medical University, Taichung, Taiwan.
Abstract:
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.
Insights
(E)-Xanthohumol (EXN) effectively targets aberrant lipid metabolism in prostate cancer (PCa) by downregulating SREBP-1/2 pathways. This natural compound suppresses PCa growth and progression, offering a potential new therapy for castration-resistant PCa (CRPC).
Area of Science:
- Biochemistry
- Oncology
- Metabolomics
Background:
- Aberrant lipid metabolism, regulated by SREBP-1 and SREBP-2, drives prostate cancer (PCa) and castration-resistant PCa (CRPC) progression.
- Targeting SREBP pathways offers a dual strategy against lipogenesis and androgen receptor (AR) signaling in PCa.
- (E)-Xanthohumol (EXN), a natural chalcone, is known for metabolic modulation but its role in PCa lipogenesis is unexplored.
Purpose of the Study:
- To elucidate the molecular mechanisms of EXN's action on dysregulated lipid metabolism in PCa cells.
- To determine the efficacy of EXN against PCa aggressiveness in vitro and in vivo.
- To evaluate EXN as a potential therapeutic agent for PCa, particularly CRPC.
Main Methods:
- In vitro studies on androgen-dependent and CRPC PCa cell lines assessing growth, migration, invasion, and apoptosis.
- Western blot analysis to evaluate the expression of SREBP-1, SREBP-2, FASN, HMGCR, and AR.
- Lipidomic analysis to quantify triglycerides and cholesterol esters.
- In vivo studies using nude mice xenograft models to assess tumor growth attenuation.
Main Results:
- EXN significantly inhibited PCa cell growth, migration, and invasion, while inducing apoptosis.
- EXN downregulated the expression of SREBP-1, SREBP-2, FASN, HMGCR, and AR.
- Lipidomic analysis revealed decreased triglycerides and cholesterol esters in PCa cells treated with EXN.
- EXN treatment led to the attenuation of CRPC tumor growth in vivo.
Conclusions:
- EXN demonstrates significant anti-prostate cancer activity by targeting SREBP-mediated lipid metabolism.
- EXN effectively suppresses PCa cell aggressiveness and CRPC tumor growth.
- EXN represents a novel therapeutic candidate for PCa, potentially overcoming limitations of current hormonal therapies.
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