title: Selective Vulnerability of Cancer Cells by Inhibition of Ca(2+) Transfer from Endoplasmic Reticulum to Mitochondria.
abstract: In the absence of low-level ER-to-mitochondrial Ca(2+) transfer, ATP levels fall, and AMPK-dependent, mTOR-independent autophagy is induced as an essential survival mechanism in many cell types. Here, we demonstrate that tumorigenic cancer cell lines, transformed primary human fibroblasts, and tumors in vivo respond similarly but that autophagy is insufficient for survival, and cancer cells die while their normal counterparts are spared. Cancer cell death is due to compromised bioenergetics that can be rescued with metabolic substrates or nucleotides and caused by necrosis associated with mitotic catastrophe during their proliferation. Our findings reveal an unexpected dependency on constitutive Ca(2+) transfer to mitochondria for viability of tumorigenic cells and suggest that mitochondrial Ca(2+) addiction is a feature of cancer cells.
authors.affiliation: Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, Geroscience Center for Brain Health and Metabolism, University of Chile, Santiago, Chile. Electronic address: jcesar@u.uchile.cl.
authors.forename: César
authors.initials: C
authors.lastname: Cárdenas
authors.affiliation: Department of Medical Technology, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Marioly
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: McNeal
authors.affiliation: Center for Neuroscience Research, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Alenka
authors.initials: A
authors.lastname: Lovy
authors.affiliation: Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, Geroscience Center for Brain Health and Metabolism, University of Chile, Santiago, Chile.
authors.forename: Fabian
authors.initials: F
authors.lastname: Jaňa
authors.affiliation: Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, Geroscience Center for Brain Health and Metabolism, University of Chile, Santiago, Chile.
authors.forename: Galdo
authors.initials: G
authors.lastname: Bustos
authors.affiliation: Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, Geroscience Center for Brain Health and Metabolism, University of Chile, Santiago, Chile.
authors.forename: Felix
authors.initials: F
authors.lastname: Urra
authors.affiliation: Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, Geroscience Center for Brain Health and Metabolism, University of Chile, Santiago, Chile.
authors.forename: Natalia
authors.initials: N
authors.lastname: Smith
authors.affiliation: CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Laboratoire de Toxinologie Moléculaire et Biotechnologies, Bâtiment 152, Courrier Number 24, 91191 Gif-sur-Yvette, France.
authors.forename: Jordi
authors.initials: J
authors.lastname: Molgó
authors.affiliation: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Ridky
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: foskett@mail.med.upenn.edu.
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Foskett
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000111:Acetylcysteine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000494:pharmacology; D018715:Microscopy, Video; D008928:Mitochondria / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D010080:Oxazoles; D034741:RNA, Small Interfering; C078549:xestospongin B; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D002118:Calcium; D000111:Acetylcysteine