title: A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy.
abstract: Killing cancer cells through the induction of apoptosis is one of the main mechanisms of chemotherapy. However, numerous cancer cells have primary or acquired apoptosis resistance, resulting in chemoresistance. In this study, using a novel chalcone derivative chalcone-24 (Chal-24), we identified a novel anticancer mechanism through autophagy-mediated necroptosis (RIP1- and RIP3-dependent necrosis). Chal-24 potently killed different cancer cells with induction of necrotic cellular morphology while causing no detectable caspase activation. Blocking the necroptosis pathway with either necrostatin-1 or by knockdown of RIP1 and RIP3 effectively blocked the cytotoxicity of Chal-24, suggesting that Chal-24-induced cell death is associated with necroptosis. Chal-24 robustly activated JNK and ERK and blockage of which effectively suppressed Chal-24-induced cytotoxicity. In addition, Chal-24 strongly induced autophagy that is dependent on JNK-mediated phosphorylation of Bcl-2 and Bcl-xL and dissociation of Bcl-2 or Bcl-xL from Beclin-1. Importantly, suppression of autophagy, with either pharmacological inhibitors or small interfering RNAs targeting the essential autophagy components ATG7 and Beclin-1, effectively attenuated Chal-24-induced cell death. Furthermore, we found that autophagy activation resulted in c-IAP1 and c-IAP2 degradation and formation of the Ripoptosome that contributes to necroptosis. These results thus establish a novel mechanism for killing cancer cells that involves autophagy-mediated necroptosis, which may be employed for overcoming chemoresistance.
authors.affiliation: 1] Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA [2] Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: W
authors.initials: W
authors.lastname: He
authors.affiliation: 1] Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA [2] Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
authors.forename: B
authors.initials: B
authors.lastname: Srinivasan
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Padilla
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: X
authors.initials: X
authors.lastname: Gou
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: H-M
authors.initials: HM
authors.lastname: Shen
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
authors.forename: C
authors.initials: C
authors.lastname: Xing
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D000071186:Beclin-1; D045744:Cell Line, Tumor; D047188:Chalcones / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: C576272:3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one; C119724:AGFG1 protein, human; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D047188:Chalcones; D007093:Imidazoles; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D028861:Nuclear Pore Complex Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C507699:necrostatin-1; C494833:BIRC2 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes