Oncotarget

Research Papers:

Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics

Takuro Ishikawa, Yoshinao Z. Hosaka, Colin Beckwitt, Alan Wells, Zoltán N. Oltvai and Katsuhiko Warita _

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Oncotarget. 2018; 9:29304-29315. https://doi.org/10.18632/oncotarget.25448

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Abstract

Takuro Ishikawa1,2, Yoshinao Z. Hosaka1,2, Colin Beckwitt3, Alan Wells3,4, Zoltán N. Oltvai3,4 and Katsuhiko Warita1,2

1Laboratory of Basic Veterinary Science, United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi 753-8515, Japan

2Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori 680-8553, Japan

3Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA

4Department of Computational & Systems Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15260, USA

Correspondence to:

Katsuhiko Warita, email: waritak@muses.tottori-u.ac.jp

Zoltán N. Oltvai, email: oltvai@pitt.edu

Keywords: cell metabolism; statin; metastasis; combination therapy; cancer therapy

Received: January 06, 2018     Accepted: May 01, 2018     Published: June 29, 2018

ABSTRACT

HMG-CoA reductase (HMGCR) inhibitors, statins, are potent cholesterol reducing drugs that exhibit anti-tumor effects in vitro and in animal models, including attenuation of metastasis formation, and their use correlates with reduced cancer-specific mortality in retrospective human cohort studies. However, E-cadherin expressing epithelial- and mixed epithelial-mesenchymal cancer cell lines (reflective of primary and outgrowing metastatic tumor cells, respectively) require higher statin concentrations than mesenchymal-like tumor cells (reflective of in-circulation metastatic tumor cells) to achieve the same degree of growth inhibition. Here, we show that attenuation of HMGCR expression in the presence of atorvastatin leads to stronger growth inhibition than dual target blockade of the mevalonate pathway in relatively statin resistant cell lines, mainly through inhibition of protein prenylation pathways. Thus, combined inhibition of the mevalonate pathway’s rate-limiting enzyme, HMGCR, can improve atorvastatin’s growth inhibitory effect on epithelial- and mixed mesenchymal-epithelial cancer cells, a finding that may have implications for the design of future anti-metastatic cancer therapies.


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