title: Ouabain downregulates Mcl-1 and sensitizes lung cancer cells to TRAIL-induced apoptosis.
abstract: Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a prerequisite for cancer progression, and TRAIL resistance is prevalent in lung cancer. Ouabain, a recently identified human hormone, has shown therapeutic promise by potentiating the apoptotic response of metastatic lung cancer cells to TRAIL. Nontoxic concentrations of ouabain are shown to increase caspase-3 activation, poly(ADP-ribose) polymerase (PARP) cleavage, and apoptosis of H292 cells in response to TRAIL. While ouabain had a minimal effect on c-FLIP, Bcl-2, and Bax levels, we show that it possesses an ability to downregulate the antiapoptotic Mcl-1 protein. The present study also reveals that the sensitizing effect of ouabain is associated with its ability to generate reactive oxygen species (ROS), and hydrogen peroxide is identified as the principle ROS triggering proteasomal Mcl-1 degradation. In summary, our results indicate a novel function for ouabain in TRAIL-mediated cancer cell death through Mcl-1 downregulation, thereby providing new insight into a potential lung cancer treatment as well as a better understanding of the physiological activity of ouabain.
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Pithi
authors.initials: P
authors.lastname: Chanvorachote
authors.forename: Varisa
authors.initials: V
authors.lastname: Pongrakhananon
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010042:Ouabain / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014162:Transfection; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D025801:Ubiquitin; D010042:Ouabain; D006861:Hydrogen Peroxide; D046988:Proteasome Endopeptidase Complex