Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Sacramento, CA, USA.
Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Sacramento, CA, USA; UC Davis Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, USA; VA Northern California Health Care System, Mather, CA, USA.
Biochem Pharmacol. 2022 Feb;196:114725. doi: 10.1016/j.bcp.2021.114725. Epub 2021 Aug 9.
Aberrant cholesterol metabolism and homeostasis in the form of elevated cholesterol biosynthesis and dysregulated efflux and metabolism is well recognized as a major feature of metabolic reprogramming in solid tumors. Recent studies have emphasized on major drivers and regulators such as Myc, mutant p53, SREBP2, LXRs and oncogenic signaling pathways that play crucial roles in tumor cholesterol metabolic reprogramming. Therapeutics such as statins targeting the mevalonate pathway were tried at the clinic without showing consistent benefits to cancer patients. Nuclear receptors are prominent regulators of mammalian metabolism. Their de-regulation often drives tumorigenesis. RORγ and its immune cell-specific isoform RORγt play important functions in control of mammalian metabolism, circadian rhythm and immune responses. Although RORγ, together with its closely related members RORα and RORβ were identified initially as orphan receptors, recent studies strongly support the conclusion that specific intermediates and metabolites of cholesterol pathways serve as endogenous ligands of RORγ. More recent studies also reveal a critical role of RORγ in tumorigenesis through major oncogenic pathways including acting a new master-like regulator of tumor cholesterol biosynthesis program. Importantly, an increasing number of RORγ orthosteric and allosteric ligands are being identified that display potent activities in blocking tumor growth and autoimmune disorders in preclinical models. This review summarizes the recent preclinical and clinical progress on RORγ with emphasis on its role in reprogramming tumor cholesterol metabolism and its regulation. It will also discuss RORγ functional mechanisms, context-specificity and its value as a therapeutic target for effective cancer treatment.
异常的胆固醇代谢和稳态，表现为胆固醇生物合成升高和外排及代谢失调，这是实体瘤代谢重编程的一个主要特征。最近的研究强调了一些主要的驱动因素和调节因子，如 Myc、突变型 p53、SREBP2、LXRs 和致癌信号通路，它们在肿瘤胆固醇代谢重编程中发挥着关键作用。以甲羟戊酸途径为靶点的他汀类药物等治疗方法在临床上进行了尝试，但对癌症患者并没有显示出一致的益处。核受体是哺乳动物代谢的主要调节因子。它们的失调往往会导致肿瘤发生。RORγ及其免疫细胞特异性同工型 RORγt 在控制哺乳动物代谢、昼夜节律和免疫反应方面发挥着重要作用。虽然 RORγ 与其密切相关的成员 RORα 和 RORβ 最初被鉴定为孤儿受体，但最近的研究强烈支持胆固醇途径的特定中间产物和代谢物作为 RORγ 的内源性配体的结论。最近的研究还揭示了 RORγ 通过包括作为肿瘤胆固醇生物合成程序的新主样调节因子在内的主要致癌途径在肿瘤发生中的关键作用。重要的是，越来越多的 RORγ 正构和别构配体被鉴定出来，它们在临床前模型中显示出抑制肿瘤生长和自身免疫性疾病的强大活性。本综述总结了 RORγ 的最新临床前和临床进展，重点介绍了它在重新编程肿瘤胆固醇代谢及其调节中的作用。它还将讨论 RORγ 的功能机制、特异性和作为癌症治疗有效靶点的价值。
