Aberrant DNA Damage Response and DNA Repair Pathway in High Glucose Conditions
DOI:
https://doi.org/10.6000/1929-2279.2018.07.03.1Keywords:
Diabetes, DNA damage response, ATR, checkpoint kinase 1, Chemo resistant.Abstract
Background: Higher cancer rates and more aggressive behavior of certain cancers have been reported in populations with diabetes mellitus. This association has been attributed in part to the excessive reactive oxygen species generated in diabetic conditions and to the resulting oxidative DNA damage. It is not known, however, whether oxidative stress is the only contributing factor to genomic instability in patients with diabetes or whether high glucose directly also affects DNA damage and repair pathways.
Results: Normal renal epithelial cells and renal cell carcinoma cells are more chemo- and radiation resistant when cultured in high concentrations of glucose. In high glucose conditions, the CHK1-mediated DNA damage response is not activated properly. Cells in high glucose also have slower DNA repair rates and accumulate more mutations than cells grown in normal glucose concentrations. Ultimately, these cells develop a transforming phenotype.
Conclusions: In high glucose conditions, defective DNA damage responses most likely contribute to the higher mutation rate in renal epithelial cells, in addition to oxidative DNA damage. The DNA damage and repair are normal enzyme dependent mechanisms requiring euglycemic environments. Aberrant DNA damage response and repair in cells grown in high glucose conditions underscore the importance of maintaining good glycemic control in patients with diabetes mellitus and cancer.
References
Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. Diabetes Care 2010; 33: 1674-85. https://doi.org/10.2337/dc10-0666
Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr Relat Cancer 2009; 16: 1103-23. https://doi.org/10.1677/ERC-09-0087
Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005; 54: 1615-25. https://doi.org/10.2337/diabetes.54.6.1615
Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature 2004; 432: 316-323. https://doi.org/10.1038/nature03097
Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature 2000; 408: 433-9. https://doi.org/10.1038/35044005
Khanna KK, Jackson SP. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 2001; 27: 247-54. https://doi.org/10.1038/85798
Hruda J, Sramek V, Leverve X. High glucose increases susceptibility to oxidative-stress-induced apoptosis and DNA damage in K-562 cells. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2010; 154: 315-20. https://doi.org/10.5507/bp.2010.047
Lorenzi M, Montisano DF, Toledo S, Barrieux A. High glucose induces DNA damage in cultured human endothelial cells. J Clin Invest 1986; 77: 322-5. https://doi.org/10.1172/JCI112295
Yang S, Chintapalli J, Sodagum L, Baskin S, Malhotra A, Reiss K, Meggs LG. Activated IGF-1R inhibits hyperglycemia-induced DNA damage and promotes DNA repair by homologous recombination. Am J Physiol Renal Physiol 2005; 289: F1144-52. https://doi.org/10.1152/ajprenal.00094.2005
Zhang Y, Zhou J, Wang T, Cai L. High level glucose increases mutagenesis in human lymphoblastoid cells. Int J Biol Sci 2007; 3: 375-9. https://doi.org/10.7150/ijbs.3.375
Wu J, Yan LJ. Streptozotocin-induced type 1 diabetes in rodents as a model for studying mitochondrial mechanisms of diabetic beta cell glucotoxicity. Diabetes Metab Syndr Obes 2015; 8: 181-8.
Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 2001; 50: 537-46.
Wood IS, Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr 2003; 89: 3-9. https://doi.org/10.1079/BJN2002763
Kohler SW, Provost GS, Fieck A, Kretz PL, Bullock WO, Sorge JA, Putman DL, Short JM. Spectra of spontaneous and mutagen-induced mutations in the lacI gene in transgenic mice. Proc Natl Acad Sci U S A 1991; 88: 7958-62. https://doi.org/10.1073/pnas.88.18.7958
Nishino H, Buettner VL, Haavik J, Schaid DJ, Sommer SS. Spontaneous mutation in Big Blue transgenic mice: analysis of age, gender, and tissue type. Environ Mol Mutagen 1996; 28: 299-312. https://doi.org/10.1002/(SICI)1098-2280(1996)28:4<299::AID-EM2>3.0.CO;2-7
Polci R, Peng A, Chen PL, Riley DJ, Chen Y. NIMA-related protein kinase 1 is involved early in the ionizing radiation- induced DNA damage response. Cancer Res 2004; 64: 8800-3. https://doi.org/10.1158/0008-5472.CAN-04-2243
Chen Y, Chiang HC, Litchfield P, Pena M, Juang C, Riley DJ. Expression of Nek1 during kidney development and cyst formation in multiple nephron segments in the Nek1-deficient kat2J mouse model of polycystic kidney disease. J Biomed Sci 2014; 21: 63. https://doi.org/10.1186/s12929-014-0063-5
Chen Y, Chen CF, Chiang HC, Pena M, Polci R, Wei RL, Edwards RA, Hansel DE, Chen PL, Riley DJ. Mutation of NIMA-related kinase 1 (NEK1) leads to chromosome instability. Mol Cancer 2011; 10: 5. https://doi.org/10.1186/1476-4598-10-5
Chen PL, Chen YM, Bookstein R, Lee WH. Genetic mechanisms of tumor suppression by the human p53 gene. Science 1990; 250: 1576-80. https://doi.org/10.1126/science.2274789
Chen YM, Chen PL, Arnaiz N, Goodrich D, Lee WH. Expression of wild-type p53 in human A673 cells suppresses tumorigenicity but not growth rate. Oncogene 1991; 6: 1799-805.
Siska PJ, Beckermann KE, Rathmell WK, Haake SM. Strategies to overcome therapeutic resistance in renal cell carcinoma. Urol Oncol 2017; 35: 102-110. https://doi.org/10.1016/j.urolonc.2016.12.002
Blanco AI, Teh BS, Amato RJ. Role of radiation therapy in the management of renal cell cancer. Cancers (Basel) 2011; 3: 4010-23. https://doi.org/10.3390/cancers3044010
Chen Y, Chen CF, Polci R, Wei R, Riley DJ, Chen PL. Increased Nek1 expression in renal cell carcinoma cells is associated with decreased sensitivity to DNA-damaging treatment. Oncotarget 2014; 5: 4283-94. https://doi.org/10.18632/oncotarget.2005
Callaghan MJ, Ceradini DJ, Gurtner GC. Hyperglycemia-induced reactive oxygen species and impaired endothelial progenitor cell function. Antioxid Redox Signal 2005; 7: 1476-82. https://doi.org/10.1089/ars.2005.7.1476
Felice F, Lucchesi D, di Stefano R, Barsotti MC, Storti E, Penno G, Balbarini A, Del Prato S, Pucci L. Oxidative stress in response to high glucose levels in endothelial cells and in endothelial progenitor cells: evidence for differential glutathione peroxidase-1 expression. Microvasc Res 2010; 80: 332-8. https://doi.org/10.1016/j.mvr.2010.05.004
Russell JW, Golovoy D, Vincent AM, Mahendru P, Olzmann JA, Mentzer A, Feldman EL. High glucose-induced oxidative stress and mitochondrial dysfunction in neurons. FASEB J 2002; 16(13): 1738-48. https://doi.org/10.1096/fj.01-1027com
Chen Y, Chen CF, Riley DJ, Chen PL: Nek1 kinase functions in DNA damage response and checkpoint control through a pathway independent of ATM and ATR. Cell Cycle 2011; 10: 655-63. https://doi.org/10.4161/cc.10.4.14814
Chen Y, Craigen WJ, Riley DJ. Nek1 regulates cell death and mitochondrial membrane permeability through phosphorylation of VDAC1. Cell Cycle 2009; 8: 257-67. https://doi.org/10.4161/cc.8.2.7551
Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 2004; 159: 1160-7. https://doi.org/10.1093/aje/kwh161
Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell 2010; 40: 179-204. https://doi.org/10.1016/j.molcel.2010.09.019
Elledge SJ. Cell cycle checkpoints: preventing an identity crisis. Science 1996; 274: 1664-72. https://doi.org/10.1126/science.274.5293.1664
Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A et al. Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev 2000; 14: 1448-59.
Xu N, Libertini S, Black EJ, Lao Y, Hegarat N, Walker M, Gillespie DA. Cdk-mediated phosphorylation of Chk1 is required for efficient activation and full checkpoint proficiency in response to DNA damage. Oncogene 2012; 31: 1086-94. https://doi.org/10.1038/onc.2011.310
Downloads
Published
How to Cite
Issue
Section
