title: Inhibition of autophagy enhances dynamin inhibitor-induced apoptosis via promoting Bak activation and mitochondrial damage in human Jurkat T cells.
abstract: Treatment of Jurkat T cells with the dynamin inhibitor, myristyl trimethyl ammonium bromides (MiTMAB) caused cytokinesis impairment and apoptotic DNA fragmentation along with down-regulation of anti-apoptotic BAG3 and Mcl-1 levels, Bak activation, mitochondrial membrane potential (Δψm) loss, activation of caspase-9 and -3, and PARP cleavage, without accompanying necrosis. Bcl-xL overexpression completely abrogated these MiTMAB-induced mitochondrial damage and resultant caspase cascade activation, except for impaired cytokinesis and down-regulated BAG3 and Mcl-1 levels. Additionally, autophagic responses including Akt-mTOR pathway inhibition, formation of acridine orange-stainable acidic vesicular organelles, LC3-I/II conversion, and p62/SQSTM1 down-regulation were detected regardless of Bcl-xL overexpression. The autophagy inhibitors 3-methyladenine and LY294002 enhanced MiTMAB-induced apoptotic sub-G1 peak, BAG3 and Mcl-1 down-regulation, Bak activation, Δψm loss, and caspase activation. These results indicate that MiTMAB-caused cytokinesis failure leads to concomitant induction of apoptosis and cytoprotective autophagy, and suggest that inhibition of autophagy is a promising strategy to augment antitumor activity of MiTMAB.
authors: Laboratory of Immunobiology, School of Life Science and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea; Daegu Science High School, Daegu, 41566, South Korea.
authors: Yoon
authors: Y
authors: Hee Kim
authors: Laboratory of Immunobiology, School of Life Science and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea.
authors: Ki Yun
authors: KY
authors: Kim
authors: Laboratory of Immunobiology, School of Life Science and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea.
authors: Do Youn
authors: do Y
authors: Jun
authors: Department of Biological Sciences, Andong National University, Andong, 36729, South Korea.
authors: Jong-Sik
authors: JS
authors: Kim
authors: Laboratory of Immunobiology, School of Life Science and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea. Electronic address: ykim@knu.ac.kr.
authors: Young Ho
authors: YH
authors: Kim
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D050337:Trimethyl Ammonium Compounds / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*
chemical_list: D017304:Annexin A5; D002867:Chromones; D009025:Morpholines; D050337:Trimethyl Ammonium Compounds; D050998:bcl-2 Homologous Antagonist-Killer Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C025946:3-methyladenine; D020169:Caspases; D034281:Dynamins; D016650:Fluorescein-5-isothiocyanate; D000225:Adenine; C009410:tetradecyltrimethylammonium
keywords: BAG3 and Mcl-1 down-regulation; Cytokinesis arrest; Cytoprotective autophagy; Dynamin inhibitor; MiTMAB; Mitochondrial apoptosis