title: Rotenone induces apoptosis in human lung cancer cells by regulating autophagic flux.
abstract: Reactive oxygen species (ROS) are at the center of many physiological and pathological processes. ROS generated due to oxidative stress can potentiate both cancer initiation and progression. Rotenone, which is an inhibitor of the mitochondrial electron transport chain complex I, results in the activation of NOX2 and release of ROS, and has been shown to display anticancer activity through the induction of apoptosis in various cancer cells. The mechanistic link between rotenone-dependent activation of NOX2 and induction of apoptosis is still elusive. In this study, we used the human lung cancer A549 cells to study the molecular mechanism(s) involved between rotenone-dependent activation of NOX2 and impairment of autophagic machinery. We report that acute exposure to rotenone induced mild NOX2-dependnet oxidative stress, which impaired the autophagic flux, resulting in cytosolic accumulation of LC3 and p62/STSQM1. We further show that this induction occurs through the PI3K/Akt/mTORC1 signaling pathway. We furthermore show that chronic exposure to rotenone lead to excessive NOX2-dependent ROS generation, increases autophagy, and decreases p62 level via increased-autophagic flux. Taken together, this study is the first mechanistic elucidation of how rotenone can be used to potently target cancer cells without overhauling the entire cellular machinery. © 2016 IUBMB Life 68(5):388-393, 2016.
authors.affiliation: Department of Thoracic Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Wensi
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Thoracic Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Thoracic Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Yue
authors.affiliation: Department of Thoracic Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Thoracic Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Shuhai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Thoracic Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Cun
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Thoracic Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Si
authors.affiliation: Department of Thoracic Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Qi
authors.affiliation: Department of Thoracic Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Thoracic Surgery, Central Hospital of ZiBo, ZiBo, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hao
authors.affiliation: Department of Thoracic Surgery, Central Hospital of ZiBo, ZiBo, China.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Shan
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms; D000076222:Mechanistic Target of Rapamycin Complex 1; D008562:Membrane Glycoproteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000076222:Mechanistic Target of Rapamycin Complex 1; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D012402:Rotenone; D058570:TOR Serine-Threonine Kinases; C056558:CYBB protein, human
keywords: A549 cells; human lung cancer; oxidative stress