title: Non-cell-autonomous Effects of Autophagy Inhibition in Tumor Cells Promote Growth of Drug-resistant Cells.
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 E2signaling. 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.
authors.affiliation: 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.).
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Thorburn
authors.affiliation: 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.).
authors.forename: Leah
authors.initials: L
authors.lastname: Staskiewicz
authors.affiliation: 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.).
authors.forename: Megan L
authors.initials: ML
authors.lastname: Goodall
authors.affiliation: 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.).
authors.forename: Lina
authors.initials: L
authors.lastname: Dimberg
authors.affiliation: 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.).
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Frankel
authors.affiliation: 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.).
authors.forename: Heide L
authors.initials: HL
authors.lastname: Ford
authors.affiliation: 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.
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071183:Autophagy-Related Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004167:Diphtheria Toxin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology
chemical_list: D000071183:Autophagy-Related Proteins; D004167:Diphtheria Toxin; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D049452:Green Fluorescent Proteins; D004815:Epidermal Growth Factor