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Mol Pharmacol. 2017 Jan;91(1):58-64. Epub 2016 Nov 9.

Non-cell-autonomous Effects of Autophagy Inhibition in Tumor Cells Promote Growth of Drug-resistant Cells.

Author information

1
Department. of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado (J.T., L.S., M.L.G., L.D., H.L.F., A.T.); and Department of Medicine, University of Texas Southwest Medical School, Dallas, Texas (A.E.F.).
2
Department. of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado (J.T., L.S., M.L.G., L.D., H.L.F., A.T.); and Department of Medicine, University of Texas Southwest Medical School, Dallas, Texas (A.E.F.) Andrew.Thorburn@ucdenver.edu.

Abstract

Autophagy, the mechanism by which cells deliver material to the lysosome, has been associated with resistance to anticancer drugs, leading autophagy inhibition to be widely studied as a potential chemosensitization strategy for cancer cells. This strategy is based on the idea that inhibition of autophagy will increase drug sensitivity and kill more cancer cells. Here we report an unintended negative effect of this strategy. When modeling the effect of drug resistance in a heterogeneous cancer cell population, we found that autophagy inhibition in drug-sensitive tumor cells causes increased growth of drug-resistant cells in the population through a mechanism involving caspase activation and prostaglandin E2 signaling. These results emphasize the importance of understanding how autophagy manipulation in a tumor cell can have both cell-autonomous and nonautonomous effects and suggest that attempts to chemosensitize by inhibiting autophagy could be enhanced by adopting methods aimed at reducing tumor repopulation.

PMID:
27974637
PMCID:
PMC5198514
DOI:
10.1124/mol.116.106070
[Indexed for MEDLINE]
Free PMC Article

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