Department of Pharmacology, School of Pharmacy, Qingdao University, No. 38 Dengzhou Street, Qingdao, 266021, China.
Fundam Clin Pharmacol. 2020 Feb;34(1):4-10. doi: 10.1111/fcp.12495. Epub 2019 Jul 15.
Emerging epidemiological and preclinical studies have focused on statins and mevalonate pathway to identify potential therapeutic target and clarify the underlying mechanism of the anti-neoplastic effects. Reductions of mevalonate or isoprenoids, caused by statins, would further decrease the isoprenylation of Rho GTPases which is the crucial step for Rho GTPases to anchor on inner cellular membrane. Following anchoring, activated Rho GTPases can mediate a series of cellular activities such as cytoskeleton reprogramming, front-rear polarity, and cell-ECM adhesion. These changes not only facilitate tumor cell detachment and migration but also bring great mechanical changes to directly activate YAP, the major nuclear mechanotransducer, to translocate into nucleus. Recently, statins have been identified as potent inhibitors of YAP. Once entering nucleus, YAP would combine TEADs to promote the transcription of about 100 genes, which are involved in cell proliferation, cell cycle regulation, stemness, invasion, and metastasis. Besides, statins are able to promote the degradation of misfolded mutant p53 (mutp53), which is an oncogene in a variety of human malignancies. Reduction in mevalonate-5-phosphate (MVP), also induced by statins, would impair the stability of DNAJA1-mutp53 complex; then, elevated C terminus of Hsc70-interacting protein (CHIP) mediates the nuclear export and degradation of misfolded mutp53 through ubiquitin-proteasome pathway. It is worth noted that YAP, mutp53, and mevalonate pathway form two positive feedback loops. It is reasonable to believe that Rho GTPases, YAP, and mutp53 are determinants for statins as anti-cancer agents: tumor cells harboring mutp53 and nuclear-located YAP would be more sensitive to statins.
新兴的流行病学和临床前研究集中在他汀类药物和甲羟戊酸途径，以确定潜在的治疗靶点并阐明其抗肿瘤作用的潜在机制。他汀类药物引起的甲羟戊酸或异戊烯的减少会进一步降低 Rho GTPases 的异戊烯化，这是 Rho GTPases 锚定在内质网膜上的关键步骤。锚定后，激活的 Rho GTPases 可以介导一系列细胞活动，如细胞骨架重编程、前后极性和细胞-细胞外基质黏附。这些变化不仅促进肿瘤细胞的脱落和迁移，而且直接激活 YAP（主要的核机械转导子），使其易位到核内，从而带来巨大的机械变化。最近，他汀类药物已被确定为 YAP 的有效抑制剂。一旦进入细胞核，YAP 就会与 TEADs 结合，促进大约 100 个基因的转录，这些基因参与细胞增殖、细胞周期调控、干细胞特性、侵袭和转移。此外，他汀类药物能够促进错误折叠的突变型 p53（mutp53）的降解，突变型 p53 是多种人类恶性肿瘤中的癌基因。他汀类药物还会诱导甲羟戊酸-5-磷酸（MVP）的减少，从而破坏 DNAJA1-mutp53 复合物的稳定性；然后，升高的热休克蛋白 70 相互作用蛋白（CHIP）通过泛素-蛋白酶体途径介导错误折叠的 mutp53 的核输出和降解。值得注意的是，YAP、mutp53 和甲羟戊酸途径形成两个正反馈环。可以合理地认为，Rho GTPases、YAP 和 mutp53 是他汀类药物作为抗癌药物的决定因素：携带 mutp53 和核定位 YAP 的肿瘤细胞对他汀类药物更为敏感。
