title: Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells.
abstract: We have investigated mechanisms of mitochondrial stress-induced phenotypic changes and cell invasion in tumorigenic but poorly invasive human pulmonary carcinoma A549 cells that were partly depleted of mitochondrial DNA (mtDNA). Depletion of mtDNA (genetic stress) caused a markedly lower electron transport-coupled ATP synthesis, loss of mitochondrial membrane potential, elevation of steady state [Ca(2+)](c), and notably induction of both glycolysis and gluconeogenic pathway enzymes. Markers of tumor invasion, cathepsin L and TGFbeta1, were overexpressed; calcium-dependent MAP kinases (ERK1 and ERK2) and calcineurin were activated. The levels of anti-apoptotic proteins Bcl2 and Bcl-X(L) were increased, and the cellular levels of pro-apoptotic proteins Bid and Bax were reduced. Both mtDNA-depleted cells (genetic stress) and control cells treated with carbonyl cyanide m-chlorophenylhydrazone (metabolic stress) exhibited higher invasive behavior than control cells in a Matrigel basement membrane matrix assay system. MtDNA-depleted cells stably expressing anti-sense cathepsin L RNA, TGFbeta1 RNA, or treated with specific inhibitors showed reduced invasion. Reverted cells with 80% of control cell mtDNA exhibited marker protein levels, cell morphology and invasive property closer to control cells. Our results suggest that the mitochondria-to-nucleus signaling pathway operating through increased [Ca(2+)](c) plays an important role in cancer progression and metastasis.
authors.affiliation: Department of Animal Biology and Mari Lowe Center for Comparative Oncology School of Veterinary Medicine, University of Pennsylvania 3800 Spruce Street, Philadelphia, PA 19104-6047, USA.
authors.forename: Govindasamy
authors.initials: G
authors.lastname: Amuthan
authors.forename: Gopa
authors.initials: G
authors.lastname: Biswas
authors.forename: Hindupur K
authors.initials: HK
authors.lastname: Ananadatheerthavarada
authors.forename: Camasamudram
authors.initials: C
authors.lastname: Vijayasarathy
authors.forename: Henry M
authors.initials: HM
authors.lastname: Shephard
authors.forename: Narayan G
authors.initials: NG
authors.lastname: Avadhani
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D017209:Apoptosis; D020013:Calcium Signaling; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000633:toxicity; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics / Q000502:physiology; D003546:Cysteine Endopeptidases; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000378:metabolism; D004996:Ethidium / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D013312:Stress, Physiological / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D009363:Neoplasm Proteins; D020320:Oligoribonucleotides, Antisense; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; D004996:Ethidium