title: Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth.
abstract: One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype. Carbon monoxide (CO), one of the products of the cytoprotective molecule heme oxygenase-1 (HO-1) in cancer cells, has been implicated in carcinogenesis and therapeutic resistance. However, the functional contributions of CO and HO-1 to these processes are poorly defined. In human prostate cancers, we found that HO-1 was nuclear localized in malignant cells, with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes. Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy, with growth arrest and apoptosis induced in vivo in part through mitotic catastrophe. CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption, free radical generation, and mitochondrial collapse. Collectively, our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics, ultimately resulting in metabolic exhaustion.
authors.affiliation: Authors' Affiliations: Department of Surgery, Transplant Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Department of Clinical Sciences, Section of Urological Cancers, School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, United Kingdom; Department of Laboratory Medicine, University Hospital Malmö, Lund University, Malmö, Sweden; and Department of Medicine and Vascular Biology Center, University of Minnesota, Minneapolis, Alfama Inc., Oeiras, Portugal.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wegiel
authors.forename: David
authors.initials: D
authors.lastname: Gallo
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.forename: Clair
authors.initials: C
authors.lastname: Harris
authors.forename: John
authors.initials: J
authors.lastname: Belcher
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
authors.forename: Nuno
authors.initials: N
authors.lastname: Penacho
authors.forename: Pankaj
authors.initials: P
authors.lastname: Seth
authors.forename: Vikas
authors.initials: V
authors.lastname: Sukhatme
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Leszek
authors.initials: L
authors.lastname: Helczynski
authors.forename: Anders
authors.initials: A
authors.lastname: Bjartell
authors.forename: Jenny Liao
authors.initials: JL
authors.lastname: Persson
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D002248:Carbon Monoxide / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D002248:Carbon Monoxide