Krycer James Robert, Brown Andrew John
School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia.
Biochim Biophys Acta. 2013 Apr;1835(2):219-29. doi: 10.1016/j.bbcan.2013.01.002. Epub 2013 Jan 26.
Prostate cancer (PCa) is the most common cancer in men in developed countries. Epidemiological studies have associated high blood-cholesterol levels with an increased risk of PCa, whilst cholesterol-lowering drugs (statins) reduce the risk of advanced PCa. Furthermore, normal prostate epithelial cells have an abnormally high cholesterol content, with cholesterol levels increasing further during progression to PCa. In this review, we explore why and how this occurs. Concurrent to this observation, intense efforts have been expended in cardiovascular research to better understand the regulators of cholesterol homeostasis. Here, we apply this knowledge to elucidate the molecular mechanisms driving the accumulation of cholesterol in PCa. For instance, recent evidence from our group and others shows that major signalling players in prostate growth and differentiation, such as androgens and Akt, modulate the key transcriptional regulators of cholesterol homeostasis to enhance cholesterol levels. This includes adjusting central carbon metabolism to sustain greater lipid synthesis. Perturbations in cholesterol homeostasis appear to be maintained even when PCa approaches the advanced, 'castration-resistant' state. Overall, this provides a link between cholesterol accumulation and PCa cell growth. Given there is currently no cure for castration-resistant PCa, could cholesterol metabolism be a novel target for PCa therapy? Overall, this review presents a picture that cholesterol metabolism is important for PCa development: growth-promoting factors stimulate cholesterol accumulation, which in turn presents a possible target for chemotherapy. Consequently, we recommend future investigations, both to better elucidate the mechanisms driving this accumulation and applying it in novel chemotherapeutic strategies.
前列腺癌（PCa）是发达国家男性中最常见的癌症。流行病学研究表明，高血胆固醇水平与PCa风险增加相关，而降低胆固醇的药物（他汀类药物）可降低晚期PCa的风险。此外，正常前列腺上皮细胞的胆固醇含量异常高，在进展为PCa的过程中胆固醇水平进一步升高。在本综述中，我们探讨了其发生的原因和方式。与此同时，心血管研究领域也投入了大量精力，以更好地了解胆固醇稳态的调节因子。在此，我们运用这些知识来阐明驱动PCa中胆固醇积累的分子机制。例如，我们团队和其他团队最近的证据表明，前列腺生长和分化中的主要信号参与者，如雄激素和Akt，可调节胆固醇稳态的关键转录调节因子，以提高胆固醇水平。这包括调整中心碳代谢以维持更大的脂质合成。即使PCa发展到晚期的“去势抵抗”状态，胆固醇稳态的紊乱似乎仍会持续。总体而言，这为胆固醇积累与PCa细胞生长之间建立了联系。鉴于目前尚无治疗去势抵抗性PCa的方法，胆固醇代谢能否成为PCa治疗的新靶点？总体而言，本综述描绘了一幅胆固醇代谢对PCa发展很重要的图景：促进生长的因子刺激胆固醇积累，这反过来又可能成为化疗的靶点。因此，我们建议未来进行更多研究，以更好地阐明驱动这种积累的机制，并将其应用于新的化疗策略中。
