title: Autophagy-Mediated Degradation of IAPs and c-FLIP(L) Potentiates Apoptosis Induced by Combination of TRAIL and Chal-24.
abstract: Combination chemotherapy is an effective strategy for increasing anticancer efficacy, reducing side effects and alleviating drug resistance. Here we report that combination of the recently identified novel chalcone derivative, chalcone-24 (Chal-24), and TNF-related apoptosis-inducing ligand (TRAIL) significantly increases cytotoxicity in lung cancer cells. Chal-24 treatment significantly enhanced TRAIL-induced activation of caspase-8 and caspase-3, and the cytotoxicity induced by combination of these agents was effectively suppressed by the pan-caspase inhibitor z-VAD-fmk. Chal-24 and TRAIL combination suppressed expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (c-FLIP(L)) and cellular inhibitor of apoptosis proteins (c-IAPs), and ectopic expression of c-FLIP(L) and c-IAPs inhibited the potentiated cytotoxicity. In addition, TRAIL and Chal-24 cooperatively activated autophagy. Suppression of autophagy effectively attenuated cytotoxicity induced by Chal-24 and TRAIL combination, which was associated with attenuation of c-FLIP(L) and c-IAPs degradation. Altogether, these results suggest that Chal-24 potentiates the anticancer activity of TRAIL through autophagy-mediated degradation of c-FLIP(L) and c-IAPs, and that combination of Chal-24 and TRAIL could be an effective approach in improving chemotherapy efficacy.
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, 87108, New Mexico.
authors.forename: Jennings
authors.initials: J
authors.lastname: Xu
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, 87108, New Mexico.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Xu
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, 87108, New Mexico.|Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, 610041, P.R. China.
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Shi
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, 87108, New Mexico.|Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, 610041, P.R. China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, 87108, New Mexico.
authors.forename: Bryanna
authors.initials: B
authors.lastname: Saxton
authors.affiliation: Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 510182, P.R. China.
authors.forename: Weiyang
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 510182, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Gou
authors.affiliation: Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, 610041, P.R. China.|Division of Pulmonary and Critical Care Medicine, University of New Mexico and New Mexico VA Health Care System, Albuquerque, New Mexico.
authors.forename: Jun-Ho
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, 610041, P.R. China.|Division of Pulmonary and Critical Care Medicine, University of New Mexico and New Mexico VA Health Care System, Albuquerque, New Mexico.
authors.forename: Toru
authors.initials: T
authors.lastname: Nyunoya
authors.affiliation: Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, 610041, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, 55455, Minnesota.
authors.forename: Chengguo
authors.initials: C
authors.lastname: Xing
authors.affiliation: Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, 610041, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, 87108, New Mexico.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
mesh_terms: D000072283:A549 Cells; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: C576272:3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one; D000590:Amino Acid Chloromethyl Ketones; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D061945:Caspase Inhibitors; D047188:Chalcones; D051034:Inhibitor of Apoptosis Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D053148:Caspase 3; D053181:Caspase 8
keywords: APOPTOSIS; AUTOPHAGY; CHAL-24; TRAIL; c-FLIP; c-IAP