Effect of H(2)O(2) on cell cycle and survival in DNA mismatch repair-deficient and -proficient cell lines.
Patients who develop tumors with Lynch syndrome, which is caused by mutational inactivation of the DNA mismatch repair (MMR) system, have a relatively favorable prognosis compared to patients who develop sporadic tumors. Paradoxically, DNA MMR-deficient cells are resistant to many chemotherapeutic agents, and are capable of bypassing the G2/M checkpoint in vitro. Colon cancers that develop in the setting of Lynch syndrome show an abundant recruitment of immune cells into tumor tissues, which might be expected to increase oxyradical formation, and make the tumor cells more vulnerable to cell death. We examined the chemosensitivity and cell cycle response to oxidative stress in several MMR-deficient (HCT116, SW48, and DLD1) and -proficient (CaCo2, SW480, and HT29) colorectal cancer cell lines. H(2)O(2) induced a G2/M cell cycle arrest in both MMR deficient and proficient cell lines, however MMR-deficient cell lines were more sensitive to H(2)O(2) toxicity, and the response was more prolonged in MMR-deficient cells. Interestingly, human MutL-homologue (hMLH1-)defective HCT116 and hMLH1-restored HCT116+ch3 cell lines responded to H(2)O(2) with the same degree of G2/M arrest. The survival response of HCT116+ch3 was nearly identical to that of hMLH1-defective HCT116+ch2, although better than the response observed in HCT116 cells. In conclusion, greater cellular sensitivity and G2/M arrest in response to oxidative stress in MMR-deficient colorectal cancer cells could be one of the reasons for the more favorable prognosis seen in patients with Lynch syndrome. However, this sensitivity appears not to be a direct result of a deficient MMR function, but is more likely attributable to spectrum of target gene mutations that occurs in MMR-deficient tumors.
Chang
Dong Kyung
DK
Department of Medicine and Comprehensive Cancer Center, University of California San Diego, 4028 Basic Science Building, 9500 Gilman Drive, La Jolla 92093-0688, USA.
Goel
Ajay
A
Ricciardiello
Luigi
L
Lee
Dong Ho
DH
Chang
Christina L
CL
Carethers
John M
JM
Boland
C Richard
CR
D048868:Adaptor Proteins, Signal Transducing; D000782:Aneuploidy; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000473:pathology*; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D016195:G2 Phase / Q000187:drug effects; D017930:Genes, Reporter; D016158:Genes, p53; D049452:Green Fluorescent Proteins; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D017527:Receptor, IGF Type 2 / Q000172:deficiency / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D051028:bcl-2-Associated X Protein
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D008164:Luminescent Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017527:Receptor, IGF Type 2; D018125:Receptors, Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D000070957:MutL Protein Homolog 1