Lipophilic statins limit cancer cell growth and survival, via involvement of Akt signaling

PloS One
Colin H BeckwittAlan Wells

Abstract

The HMG-CoA reductase inhibitors, statins, have been used as lipid lowering drugs for decades and several epidemiological studies suggest statin usage correlates with a decreased incidence of cancer specific mortality in patients. However, the mechanism of this mortality benefit remains unclear. Here, we demonstrate that statin drug lipophilicity and affinity for its target enzyme, HMGCR, determine their growth suppressive potency against various tumor cell lines. The lipophilic atorvastatin decreases cancer cell proliferation and survival in vitro. Statin sensitivity coincided with Ras localization to the cytosol instead of the membrane, consistent with a decrement in prenylation. To investigate signaling pathways that may be involved with sensitivity to statin therapy, we employed inhibitors of the PI3K-Akt and Mek-Erk signaling cascades. We found that inhibition of PI3K signaling through Akt potentiated statin sensitivity of breast cancer cells in vitro and in co-culture with primary human hepatocytes. The same effect was not observed with inhibition of Mek signaling through Erk. Moreover, the sensitivity of breast cancer cells to atorvastatin-mediated growth suppression correlated with a decrease in EGF-mediated phosphoryla...Continue Reading

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Citations

Dec 17, 2019·American Journal of Clinical Oncology·Ali Fatehi Hassanabad, Jonathan V S Wong
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Dec 10, 2021·Veterinary and Comparative Oncology·Anne-Laurence VigneauMarilène Paquet

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Methods Mentioned

BETA
transfection
Assay
pull down
Protein Assay
lipidation

Software Mentioned

GraphPad Prism

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