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Key roles of Rho GTPases, YAP, and Mutant P53 in anti‐neoplastic effects of statins
Author(s) -
Ji Lixia,
Liu Chaolong,
Yuan Yanting,
Gao Hui,
Tang Zhenxue,
Yang Zhihong,
Liu Zhantao,
Jiang Guohui
Publication year - 2020
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/fcp.12495
Subject(s) - microbiology and biotechnology , mevalonate pathway , gtpase , cdc42 , biology , prenylation , mevalonic acid , nuclear export signal , small gtpase , cell migration , cell , signal transduction , biochemistry , cell nucleus , nucleus , reductase , enzyme
Abstract 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.