Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy.
Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy.
IUBMB Life. 2021 Jul;73(7):968-977. doi: 10.1002/iub.2503. Epub 2021 May 21.
Statins are inhibitors of the mevalonate pathway that besides being cholesterol lowering agents, display anti-cancer properties. This is because cholesterol is an essential component of cell membranes but also because the mevalonate pathway controls protein farnesylation and geranylation, processes essential for the activity of GTPase family proteins. In this study, we found that Lovastatin exerted a dose- and time-dependent cytotoxic effect against PEL cells, an aggressive B cell lymphoma strictly associated with the gammaherpesvirus KSHV and characterized by a poor response to conventional chemotherapies. At molecular level, Lovastatin by dephosphorylating STAT3, induced ERK1/2 activation that inhibited autophagy and phosphorylated p53ser15 that in turn maintained ERK1/2 activated and up-regulated p21. However, p21 played a pro-survival role in this setting, as its inhibition by UC2288 further reduced cell survival in PEL cells undergoing Lovastatin treatment. In conclusion, this study suggests that Lovastatin may represent a valid therapeutic alternative against PEL cells, especially if used in combination with p21 inhibitors.
他汀类药物是甲羟戊酸途径的抑制剂，除了降低胆固醇外，还具有抗癌特性。这是因为胆固醇是细胞膜的重要组成部分，但也因为甲羟戊酸途径控制着蛋白质的法呢基化和香叶基化，这是 GTP 酶家族蛋白活性所必需的过程。在这项研究中，我们发现洛伐他汀对 PEL 细胞具有剂量和时间依赖性的细胞毒性作用，PEL 细胞是一种侵袭性 B 细胞淋巴瘤，与γ疱疹病毒 KSHV 密切相关，对常规化疗反应不佳。在分子水平上，洛伐他汀通过去磷酸化 STAT3，诱导 ERK1/2 激活，抑制自噬，并磷酸化 p53ser15，从而维持 ERK1/2 的激活并上调 p21。然而，在这种情况下，p21 发挥了促进生存的作用，因为用 UC2288 抑制 p21 进一步降低了接受洛伐他汀治疗的 PEL 细胞的存活率。总之，这项研究表明，洛伐他汀可能是治疗 PEL 细胞的一种有效治疗选择，特别是如果与 p21 抑制剂联合使用。
