title: PDK2-mediated alternative splicing switches Bnip3 from cell death to cell survival.
abstract: Herein we describe a novel survival pathway that operationally links alternative pre-mRNA splicing of the hypoxia-inducible death protein Bcl-2 19-kD interacting protein 3 (Bnip3) to the unique glycolytic phenotype in cancer cells. While a full-length Bnip3 protein (Bnip3FL) encoded by exons 1-6 was expressed as an isoform in normal cells and promoted cell death, a truncated spliced variant of Bnip3 mRNA deleted for exon 3 (Bnip3Δex3) was preferentially expressed in several human adenocarcinomas and promoted survival. Reciprocal inhibition of the Bnip3Δex3/Bnip3FL isoform ratio by inhibiting pyruvate dehydrogenase kinase isoform 2 (PDK2) in Panc-1 cells rapidly induced mitochondrial perturbations and cell death. The findings of the present study reveal a novel survival pathway that functionally couples the unique glycolytic phenotype in cancer cells to hypoxia resistance via a PDK2-dependent mechanism that switches Bnip3 from cell death to survival. Discovery of the survival Bnip3Δex3 isoform may fundamentally explain how certain cells resist Bnip3 and avert death during hypoxia.
authors.affiliation: Department of Physiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6 Department of Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6.
authors.forename: Hongying
authors.initials: H
authors.lastname: Gang
authors.affiliation: Department of Physiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6 Department of Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6.
authors.forename: Rimpy
authors.initials: R
authors.lastname: Dhingra
authors.affiliation: Department of Physiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6 Department of Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6.
authors.forename: Junjun
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Physiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6 Department of Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hai
authors.affiliation: Department of Physiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6 Department of Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Aviv
authors.affiliation: Department of Physiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6 Department of Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6.
authors.forename: Victoria
authors.initials: V
authors.lastname: Margulets
authors.affiliation: Department of Biochemistry and Medical Genetics, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hamedani
authors.affiliation: Department of Anatomy and Cell Science, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6.
authors.forename: Thatchawan
authors.initials: T
authors.lastname: Thanasupawat
authors.affiliation: Department of Biochemistry and Medical Genetics, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6.
authors.forename: Etienne
authors.initials: E
authors.lastname: Leygue
authors.affiliation: Department of Anatomy and Cell Science, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klonisch
authors.affiliation: Manitoba Institute for Child Health, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6.
authors.forename: James R
authors.initials: JR
authors.lastname: Davie
authors.affiliation: Department of Physiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6 Department of Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, R2H 2A6 Lorrie@sbrc.ca.
authors.forename: Lorrie A
authors.initials: LA
authors.lastname: Kirshenbaum
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D005091:Exons / Q000502:physiology*; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: C090121:BNIP3 protein, human; D008565:Membrane Proteins; C000631430:PDK2 protein, human; D011518:Proto-Oncogene Proteins; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases