title: A H2S-Nampt dependent energetic circuit is critical to survival and cytoprotection from damage in cancer cells.
abstract: We recently demonstrated that cancer cells that recover from damage exhibit increased aerobic glycolysis, however, the molecular mechanism by which cancer cells survive the damage and show increased aerobic glycolysis remains unknown. Here, we demonstrate that diverse cancer cells that survive hypoxic or oxidative damage show rapid cell proliferation, and develop tolerance to damage associated with increased production of hydrogen sulfide (H2S) which drives up-regulation of nicotinamide phosphoribosyltransferase (Nampt). Consistent with existence of a H2S-Nampt energetic circuit, in damage recovered cancer cells, H2S, Nampt and ATP production exhibit a significant correlation. Moreover, the treatment of cancer cells with H2S donor, NaHS, coordinately increases Nampt and ATP levels, and protects cells from drug induced damage. Inhibition of cystathionine beta synthase (CBS) or cystathionase (CTH), enzymes which drive generation of H2S, decreases Nampt production while suppression of Nampt pathway by FK866, decreases H2S and ATP levels. Damage recovered cells isolated from tumors grown subcutaneously in athymic mice also show increased production of H2S, Nampt and ATP levels, associated with increased glycolysis and rapid proliferation. Together, these data show that upon recovery from potential lethal damage, H2S-Nampt directs energy expenditure and aerobic glycolysis in cancer cells, leads to their exponential growth, and causes a high degree of tolerance to damage. Identification of H2S-Nampt as a pathway responsible for induction of damage tolerance in cancer cells may underlie resistance to therapy and offers the opportunity to target this pathway as a means in treatment of cancer.
authors.affiliation: Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine, California, United States of America.
authors.forename: Reiko
authors.initials: R
authors.lastname: Sanokawa-Akakura
authors.affiliation: Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine, California, United States of America.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Ostrakhovitch
authors.affiliation: Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine, California, United States of America.
authors.forename: Shin
authors.initials: S
authors.lastname: Akakura
authors.affiliation: Dept of Radiological Sciences, University of California Irvine, Irvine, California, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Goodwin
authors.affiliation: Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine, California, United States of America; Dept of Radiological Sciences, University of California Irvine, Irvine, California, United States of America.
authors.forename: Siamak
authors.initials: S
authors.lastname: Tabibzadeh
mesh_terms: D000178:Acrylamides / Q000633:toxicity; D000255:Adenosine Triphosphate / Q000378:metabolism; D000332:Aerobiosis; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D016207:Cytokines / Q000502:physiology*; D004734:Energy Metabolism; D006019:Glycolysis; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000502:physiology*; D054409:Nicotinamide Phosphoribosyltransferase / Q000502:physiology*; D010880:Piperidines / Q000633:toxicity; D064726:Triple Negative Breast Neoplasms / Q000473:pathology
chemical_list: D000178:Acrylamides; D016207:Cytokines; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D009363:Neoplasm Proteins; D010880:Piperidines; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D006862:Hydrogen Sulfide