Statin-induced cancer cell death can be mechanistically uncoupled from prenylation of RAS family proteins

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Journal:

Cancer Research. 2017 Dec 11. doi: 10.1158/0008-5472.CAN-17-1231

Authors:

Yu R, Longo J, van Leeuwen JE, Mullen PJ, Ba-Alawi W, Haibe-Kains B, Penn LZ.

Abstract:

The statin family of drugs preferentially trigger tumor cell apoptosis by depleting mevalonate pathway metabolites farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are used for protein prenylation, including the oncoproteins of the RAS superfamily. However, accumulating data indicate that activation of the RAS superfamily are poor biomarkers of statin sensitivity, and the mechanism of statin-induced tumor-specific apoptosis remains unclear. Here we demonstrate that cancer cell death triggered by statins can be uncoupled from prenylation of the RAS superfamily of oncoproteins. Ectopic expression of different members of the RAS superfamily did not uniformly sensitize cells to fluvastatin, indicating that increased cellular demand for GGPP and FPP cannot explain increased statin sensitivity. While ectopic expression of HRAS increased statin sensitivity, expression of myristoylated HRAS did not rescue this effect. HRAS-induced epithelial-to-mesenchymal transition (EMT) through activation of zinc finger E-box binding homeobox 1 (ZEB1) sensitized tumor cells to the anti-proliferative activity of statins, and induction of EMT by ZEB1 was sufficient to phenocopy the increase in fluvastatin sensitivity; knocking out ZEB1 reversed this effect. Publicly available gene expression and statin sensitivity databases indicated that enrichment of EMT features was associated with increased sensitivity to statins in a large panel of cancer cell lines across multiple cancer types. These results indicate that the anti-cancer effect of statins is independent from prenylation of RAS family proteins and is associated with a cancer cell EMT phenotype.
Link: http://cancerres.aacrjournals.org/content/early/2017/12/09/0008-5472.CAN-17-1231