Simultaneous activation and inhibition of autophagy sensitizes cancer cells to chemotherapy
Journal
Oncotarget
Journal Volume
7
Journal Issue
36
Pages
58075-58088
Date Issued
2016
Author(s)
Chi, K.-H.
Wang, Y.-S.
Huang, Y.-C.
Chiang, H.-C.
Chi, M.-S.
Chi, C.-H.
Wang, H.-E.
Kao, S.-J.
Abstract
While combined chemotherapy (CT) with an autophagy inducer and an autophagy inhibitor appears paradoxical, it may provide a more effective perturbation of autophagy pathways. We used two dissimilar cell lines to test the hypothesis that autophagy is the common denominator of cell fate after CT. HA22T cells are characterized by CT-induced apoptosis and use autophagy to prevent cell death, while Huh7.5.1 cells exhibit sustained autophagic morphology after CT. Combined CT and rapamycin treatment resulted in a better combination index (CI) in Huh7.5.1 cells than combined CT and chloroquine, while the reverse was true in HA22T cells. The combination of 3 drugs (triplet drug treatment) had the best CI. After triplet drug treatment, HA22T cells switched from protective autophagy to mitochondrial membrane permeabilization and endoplasmic reticulum stress response-induced apoptosis, while Huh7.5.1 cells intensified autophagic lethality. Most importantly, both cell lines showed activation of Akt after CT, while the triplet combination blocked Akt activation through inhibition of phospholipid lipase D activity. This novel finding warrants further investigation as a broad chemosensitization strategy.
Subjects
Autophagy; Chemosensitization; Chloroquine; Rapamycin; Synthetic lethality
SDGs
Other Subjects
cell protein; chloroquine; cisplatin; docetaxel; gemcitabine; light chain 3I protein; light chain 3II protein; mitogen activated protein kinase 1; mitogen activated protein kinase 3; Myc protein; navelbine; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; nucleoporin; nucleoporin 62; phospholipase D1; protein kinase B; Raf protein; rapamycin; Ras protein; S6 kinase; unclassified drug; Vinca alkaloid; antineoplastic agent; chloroquine; MTOR protein, human; phospholipase D; protein kinase B; rapamycin; reactive oxygen metabolite; target of rapamycin kinase; Vinca alkaloid; adult; animal experiment; animal model; animal tissue; antiproliferative activity; apoptosis; Article; autophagy; cancer cell; cancer chemotherapy; cancer combination chemotherapy; cell death; cell fate; chemosensitization; controlled study; drug cytotoxicity; drug potentiation; endoplasmic reticulum stress; enzyme activation; enzyme activity; glycolysis; hepatocellular carcinoma cell line; human; human cell; liver cell carcinoma; male; middle aged; mitochondrial permeability; mouse; nonhuman; protein localization; tumor volume; animal; autophagy; cell proliferation; drug effects; drug resistance; drug screening; metabolism; mitochondrial membrane; neoplasm; nonobese diabetic mouse; SCID mouse; signal transduction; tumor cell line; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Chloroquine; Drug Resistance, Neoplasm; Drug Synergism; Endoplasmic Reticulum Stress; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Mitochondrial Membranes; Neoplasms; Phospholipase D; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vinca Alkaloids; Xenograft Model Antitumor Assays