title: Mcl-1 promotes lung cancer cell migration by directly interacting with VDAC to increase mitochondrial Ca2+ uptake and reactive oxygen species generation.
abstract: Mcl-1 is an antiapoptotic member of the Bcl-2 family frequently upregulated in non-small cell lung carcinoma (NSCLC). We now report the physiological significance of an interaction between Mcl-1 and the mitochondrial outer membrane-localized voltage-dependent anion channel (VDAC) in NSCLC cell lines. Mcl-1 bound with high affinity to VDAC1 and 3 isoforms but only very weakly to VDAC2 and binding was disrupted by peptides based on the VDAC1 sequence. In A549 cells, reducing Mcl-1 expression levels or application of VDAC-based peptides limited Ca(2+) uptake into the mitochondrial matrix, the consequence of which was to inhibit reactive oxygen species (ROS) generation. In A549, H1299 and H460 cells, both Mcl-1 knockdown and VDAC-based peptides attenuated cell migration without affecting cell proliferation. Migration was rescued in Mcl-1 knockdown cells by experimentally restoring ROS levels, consistent with a model in which ROS production drives increased migration. These data suggest that an interaction between Mcl-1 and VDAC promotes lung cancer cell migration by a mechanism that involves Ca(2+)-dependent ROS production.
authors.affiliation: Department of Physiology & Biophysics, Rosalind Franklin University of Medicine & Science, North Chicago, IL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Physiology & Biophysics, Rosalind Franklin University of Medicine & Science, North Chicago, IL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Shah
authors.affiliation: Department of Physiology & Biophysics, Rosalind Franklin University of Medicine & Science, North Chicago, IL, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Bradbury
authors.affiliation: 1] Molecular Targets Program, James Graham Brown Cancer Center, Louisville, KY, USA [2] Department of Medicine, Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Physiology & Biophysics, Rosalind Franklin University of Medicine & Science, North Chicago, IL, USA.
authors.forename: C
authors.initials: C
authors.lastname: White
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D050994:Voltage-Dependent Anion Channels; D051020:bcl-X Protein; D002118:Calcium