title: Inhibition of the vacuolar ATPase induces Bnip3-dependent  death of cancer cells and a reduction in tumor burden and  metastasis.
abstract: The pro-apoptotic protein Bnip3 is induced by hypoxia and is present in the core regions of most solid tumors. Bnip3 induces programmed necrosis by an intrinsic caspase independent mitochondrial pathway. Many tumor cells have evolved pathways to evade Bnip3-mediated death attesting to the physiological relevance of the survival threat imposed by Bnip3. We have reported that acidosis can trigger the Bnip3 death pathway in hypoxic cells therefore we hypothesized that manipulation of intracellular pH by pharmacological inhibition of the vacuolar (v)ATPase proton pump, a significant pH control pathway, may activate Bnip3 and promote death of hypoxic cells within the tumor. Here we confirm that bafilomycin A1 (BafA1), a selective vATPase inhibitor, significantly increased death of breast cancer cells in a hypoxia and Bnip3-dependent manner and significantly reduced tumor growth in MCF7 and MDA-MB-231 mouse xenografts. Combined treatment of cells with BafA1 and the ERK1/2 inhibitor U0126 further augmented cell death. Combined treatment of mice containing MDA-MB-231 xenografts with BafA1 and the ERK1/2 inhibitor sorafenib was superior to either treatment alone and supported tumor regression. BafA1 and sorafenib treatments alone reduced MDA-MB-231 cell metastasis and again the combination was significantly more effective than either treatment alone and was without apparent side effects. These results present a novel mechanism to destroy hypoxic tumor cells that may help reverse the resistance of hypoxic tumors to radiation and chemotherapy and perhaps target tumor stem cells.
authors.forename: Regina M
authors.initials: RM
authors.lastname: Graham
authors.forename: John W
authors.initials: JW
authors.lastname: Thompson
authors.forename: Keith A
authors.initials: KA
authors.lastname: Webster
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology / Q000627:therapeutic use; D015687:Cell Hypoxia; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D018942:Macrolides / Q000494:pharmacology* / Q000627:therapeutic use; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000077157:Sorafenib; D047368:Tumor Burden / Q000187:drug effects; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C090121:BNIP3 protein, human; D002070:Butadienes; D004791:Enzyme Inhibitors; D018942:Macrolides; D008565:Membrane Proteins; D009570:Nitriles; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins; C113580:U 0126; D009536:Niacinamide; C040929:bafilomycin A1; D000077157:Sorafenib; D025262:Vacuolar Proton-Translocating ATPases