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PLoS One. 2018 May 15;13(5):e0197422. doi: 10.1371/journal.pone.0197422. eCollection 2018.

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

Beckwitt CH1,2,3, Shiraha K1, Wells A1,2,3,4,5.

Author information

1
Pathology, University of Pittsburgh, Pittsburgh, PA, United States of America.
2
The University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, United States of America.
3
Pittsburgh VA Health System, Pittsburgh, PA, United States of America.
4
Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States of America.
5
Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, United States of America.

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 phosphorylation of Akt. As an increase in Akt activity has been shown to be involved in the metastasis and metastatic outgrowth of many cancer types (including breast), these data suggest a mechanism by which statins may reduce cancer specific mortality in patients.

PMID:
29763460
PMCID:
PMC5953490
DOI:
10.1371/journal.pone.0197422
[Indexed for MEDLINE]
Free PMC Article

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