title: Autophagy sensitivity of neuroendocrine lung tumor cells.
abstract: Neuroendocrine (NE) phenotypes characterize a spectrum of lung tumors, including low-grade typical and intermediate-grade atypical carcinoid, high-grade large-cell NE carcinoma and small cell lung carcinoma. Currently, no effective treatments are available to cure NE lung tumors, demanding identification of biological features specific to these tumors. Here, we report that autophagy has an important role for NE lung tumor cell proliferation and survival. We found that the expression levels of the autophagy marker LC3 are relatively high in a panel of lung tumor cell lines expressing high levels of neuron-specific enolase (NSE), a key NE marker in lung tumors. In response to bafilomycin A1 and chloroquine, NE lung tumor cells exhibited cytotoxicity whereas non-NE lung tumor cells exhibited cytostasis, indicating a distinct role of autophagy for NE lung tumor cell survival. Intriguingly, in certain NE lung tumor cell lines, the levels of processed LC3 (LC3-II) were inversely correlated with AKT activity. When AKT activity was inhibited using AKTi or MK2206, the levels of LC3-II and SQSTM1/p62 were increased. In contrast, torin 1, rapamycin or mTOR knockdown increased p62 levels, suggesting that these two pathways have opposing effects on autophagy in certain NE lung tumors. Moreover, inhibition of one pathway resulted in reduced activity of the other, suggesting that these two pathways crosstalk in the tumors. These results suggest that NE lung tumor cells share a common feature of autophagy and are more sensitive to autophagy inhibition than non-NE lung tumor cells.
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Seung-Keun
authors.initials: SK
authors.lastname: Hong
authors.forename: Jin-Hwan
authors.initials: JH
authors.lastname: Kim
authors.forename: Dmytro
authors.initials: D
authors.lastname: Starenki
authors.forename: Jong-In
authors.initials: JI
authors.lastname: Park
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000378:metabolism; D000962:Antimalarials / Q000494:pharmacology; D001343:Autophagy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002738:Chloroquine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D018942:Macrolides / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000378:metabolism; D009287:Naphthyridines / Q000494:pharmacology; D018358:Neuroendocrine Tumors / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000096:biosynthesis / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D055752:Small Cell Lung Carcinoma / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D048868:Adaptor Proteins, Signal Transducing; D000962:Antimalarials; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; C477012:MAP1LC3A protein, human; C548887:MK 2206; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D009287:Naphthyridines; D034741:RNA, Small Interfering; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D002738:Chloroquine; C040929:bafilomycin A1; D011065:Poly(ADP-ribose) Polymerases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D010751:Phosphopyruvate Hydratase; D020123:Sirolimus