RT Journal Article
SR Electronic
T1 Non cell-autonomous effects of autophagy inhibition in tumor cells promote growth of drug-resistant cells.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.116.106070
DO 10.1124/mol.116.106070
A1 Jacqueline Thorburn
A1 Leah Staskiewicz
A1 Megan L Goodall
A1 Lina Dimberg
A1 Arthur E Frankel
A1 Heide L Ford
A1 Andrew Thorburn
YR 2016
UL http://molpharm.aspetjournals.org/content/early/2016/11/09/mol.116.106070.abstract
AB Autophagy, the mechanism by which cells deliver material to the lysosome, has been associated with resistance to anti-cancer 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 non-autonomous effects, and suggest that attempts to chemosensitize by inhibiting autophagy could be enhanced by adopting methods aimed at reducing tumor repopulation.