Fhit-deficient normal and cancer cells are mitomycin C and UVC resistant

Br J Cancer. 2004 Nov 1;91(9):1669-77. doi: 10.1038/sj.bjc.6602058.

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acid Anhydride Hydrolases / genetics
  • Acid Anhydride Hydrolases / physiology*
  • Animals
  • Apoptosis* / drug effects
  • Apoptosis* / radiation effects
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Cycle* / drug effects
  • Cell Cycle* / radiation effects
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / radiation effects
  • Checkpoint Kinase 1
  • Colony-Forming Units Assay
  • DNA / drug effects
  • DNA / radiation effects
  • Drug Resistance, Neoplasm*
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Humans
  • Kidney / drug effects
  • Kidney / radiation effects
  • Kinetics
  • Mice
  • Mitomycin / adverse effects*
  • Mutation / genetics
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Radiation Tolerance*
  • Signal Transduction
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Tumor Cells, Cultured
  • Ultraviolet Rays

Substances

  • Cell Cycle Proteins
  • Neoplasm Proteins
  • fragile histidine triad protein
  • Mitomycin
  • DNA
  • Protein Kinases
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Acid Anhydride Hydrolases