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 cancerspecific 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 epithelialand mixed mesenchymal-epithelial cancer cells, a finding that may have implications for the design of future anti-metastatic cancer therapies.
Bibliographical noteFunding Information:
We thank D. Koes and A. Vogt for discussion and J.R. Chaillet for comments on the manuscript. This research was supported by a VA Merit grant and an NCATS-funded TissueChip program (TR000496) to AW, an NIH-funded T32 Training Grant program (EB001026) and F30 fellowship (F30CA199947) to CB, and JSPS KAKENHI Grant # JP26890019 and #JP16K18439 to KW.
- Cancer therapy
- Cell metabolism
- Combination therapy