Statin-induced mevalonate pathway inhibition attenuates the growth of mesenchymal-like cancer cells that lack functional E-cadherin mediated cell cohesion

Katsuhiko Warita, Tomoko Warita, Colin H. Beckwitt, Mark E. Schurdak, Alexei Vazquez, Alan Wells, Zoltán N. Oltvai

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

The cholesterol reducing drugs, statins, exhibit anti-tumor effects against cancer stem cells and various cancer cell lines, exert potent additivity or synergy with existing chemotherapeutics in animal models of cancer and may reduce cancer incidence and cancer related mortality in humans. However, not all tumor cell lines are sensitive to statins, and clinical trials have demonstrated mixed outcomes regarding statins as anticancer agents. Here, we show that statin-induced reduction in intracellular cholesterol levels correlate with the growth inhibition of cancer cell lines upon statin treatment. Moreover, statin sensitivity segregates with abundant cytosolic vimentin expression and absent cell surface E-cadherin expression, a pattern characteristic of mesenchymal-like cells. Exogenous expression of cell surface E-cadherin converts statinsensitive cells to a partially resistant state implying that statin resistance is in part dependent on the tumor cells attaining an epithelial phenotype. As metastasizing tumor cells undergo epithelial to mesenchymal transition during the initiation of the metastatic cascade, statin therapy may represent an effective approach to targeting the cells most likely to disseminate.

Original languageEnglish (US)
Article number7593
JournalScientific reports
Volume4
DOIs
StatePublished - Dec 23 2014

Bibliographical note

Funding Information:
This research was in part supported by a VA Merit grant and an NCATS-funded Tissue Chip program (TR000496) to A.W. and a National Science Foundation grant to Z.N.O.

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

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