title: Fhit-deficient normal and cancer cells are mitomycin C and UVC resistant.
abstract: To identify functions of the fragile tumour suppressor gene, FHIT, matched pairs of Fhit-negative and -positive human cancer cell clones, and normal cell lines established from Fhit -/- and +/+ mice, were stressed and examined for differences in cell cycle kinetics and survival. A larger fraction of Fhit-negative human cancer cells and murine kidney cells survived treatment with mitomycin C or UVC light compared to matched Fhit-positive cells; approximately 10-fold more colonies of Fhit-deficient cells survived high UVC doses in clonigenic assays. The human cancer cells were synchronised in G1, released into S and treated with UVC or mitomycin C. At 18 h post mitomycin C treatment approximately 6-fold more Fhit-positive than -negative cells had died, and 18 h post UVC treatment 3.5-fold more Fhit-positive cells were dead. Similar results were obtained for the murine -/- cells. After low UVC doses, the rate of DNA synthesis in -/- cells decreased more rapidly and steeply than in +/+ cells, although the Atr-Chk1 pathway appeared intact in both cell types. UVC surviving Fhit -/- cells appear transformed and exhibit >5-fold increased mutation frequency. This increased mutation burden could explain the susceptibility of Fhit-deficient cells in vivo to malignant transformation.
authors.affiliation: Department of Microbiology-Immunology, Kimmel Cancer Center, Jefferson Medical College, Philadelphia, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ottey
authors.forename: S-Y
authors.initials: SY
authors.lastname: Han
authors.forename: T
authors.initials: T
authors.lastname: Druck
authors.forename: B L
authors.initials: BL
authors.lastname: Barnoski
authors.forename: K A
authors.initials: KA
authors.lastname: McCorkell
authors.forename: C M
authors.initials: CM
authors.lastname: Croce
authors.forename: C
authors.initials: C
authors.lastname: Raventos-Suarez
authors.forename: C R
authors.initials: CR
authors.lastname: Fairchild
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: K
authors.initials: K
authors.lastname: Huebner
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D000071877:Checkpoint Kinase 1; D003114:Colony-Forming Units Assay; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000528:radiation effects; D007700:Kinetics; D051379:Mice; D016685:Mitomycin / Q000009:adverse effects*; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011836:Radiation Tolerance; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D004247:DNA; D016685:Mitomycin; D009363:Neoplasm Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000099170:Bis(5'-adenosyl)triphosphatase; C576597:ATR protein, human; C000605867:CHEK1 protein, human; C000605869:Chek1 protein, mouse