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

Warita, K., Warita, T., Beckwitt, C. H., Schurdak, M. E., Vazquez, A. , Wells, A. and Oltvai, Z. N. (2014) Statin-induced mevalonate pathway inhibition attenuates the growth of mesenchymal-like cancer cells that lack functional E-cadherin mediated cell cohesion. Scientific Reports, 4, 7593. (doi: 10.1038/srep07593) (PMID:25534349) (PMCID:PMC4274516)

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 statin- sensitive 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.

• Item Type: Articles
• Additional 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.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Vazquez, Alexei
• Authors: Warita, K., Warita, T., Beckwitt, C. H., Schurdak, M. E., Vazquez, A., Wells, A., and Oltvai, Z. N.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Scientific Reports
• Publisher: Nature Publishing Group
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2014 The Authors
• First Published: First published in Scientific Reports 4:7593
• Publisher Policy: Reproduced under a Creative Commons license