title: Mitochondrial inhibitor sensitizes non-small-cell lung carcinoma cells to TRAIL-induced apoptosis by reactive oxygen species and Bcl-X(L)/p53-mediated amplification mechanisms.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for anticancer therapy; however, non-small-cell lung carcinoma (NSCLC) cells are relatively TRAIL resistant. Identification of small molecules that can restore NSCLC susceptibility to TRAIL-induced apoptosis is meaningful. We found here that rotenone, as a mitochondrial respiration inhibitor, preferentially increased NSCLC cells sensitivity to TRAIL-mediated apoptosis at subtoxic concentrations, the mechanisms by which were accounted by the upregulation of death receptors and the downregulation of c-FLIP (cellular FLICE-like inhibitory protein). Further analysis revealed that death receptors expression by rotenone was regulated by p53, whereas c-FLIP downregulation was blocked by Bcl-X(L) overexpression. Rotenone triggered the mitochondria-derived reactive oxygen species (ROS) generation, which subsequently led to Bcl-X(L) downregulation and PUMA upregulation. As PUMA expression was regulated by p53, the PUMA, Bcl-X(L) and p53 in rotenone-treated cells form a positive feedback amplification loop to increase the apoptosis sensitivity. Mitochondria-derived ROS, however, promote the formation of this amplification loop. Collectively, we concluded that ROS generation, Bcl-X(L) and p53-mediated amplification mechanisms had an important role in the sensitization of NSCLC cells to TRAIL-mediated apoptosis by rotenone. The combined TRAIL and rotenone treatment may be appreciated as a useful approach for the therapy of NSCLC that warrants further investigation.
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Y L
authors.initials: YL
authors.lastname: Shi
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: S
authors.initials: S
authors.lastname: Feng
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.affiliation: The State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Z C
authors.initials: ZC
authors.lastname: Hua
authors.affiliation: Department of Anesthesiology and Intensive Care Unit, Changhai Hospital, Affiliated Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: J J
authors.initials: JJ
authors.lastname: Bian
authors.affiliation: 1] The State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China [2] The State Key Lab of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors.forename: W
authors.initials: W
authors.lastname: Yin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000008:administration & dosage / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D012402:Rotenone