BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

High expression of RAD51 promotes DNA damage repair and survival in KRAS-mutant lung cancer cells

  • Hu, Jinfang (Department of pharmacy, First Affiliated Hospital of Nanchang University) ;
  • Zhang, Zhiguo (Department of Oncology, Beijing Daxing District People's Hospital, Capital Medical University) ;
  • Zhao, Lei (Cancer center, Beijing Friendship Hospital, Capital Medical University) ;
  • Li, Li (Cancer center, Beijing Friendship Hospital, Capital Medical University) ;
  • Zuo, Wei (Department of respiration, First Affiliated Hospital of Nanchang University) ;
  • Han, Lei (Department of Oncology, Beijing Daxing District People's Hospital, Capital Medical University)
  • Received : 2018.09.14
  • Accepted : 2018.11.12
  • Published : 2019.02.28
Download PDF
⟨ Previous Next ⟩

Abstract

RAD51 recombinase plays a critical role in homologous recombination and DNA damage repair. Here we showed that expression of RAD51 is frequently upregulated in lung cancer tumors compared with normal tissues and is associated with poor survival (hazard ratio (HR) = 2, P = 0.0009). Systematic investigation of lung cancer cell lines revealed higher expression of RAD51 in KRAS mutant (MT) cells compared to wildtype (WT) cells. We further showed that MT KRAS, but not WT KRAS, played a critical role in RAD51 overexpression via MYC. Moreover, our results revealed that KRAS MT cells are highly dependent on RAD51 for survival and depletion of RAD51 resulted in enhanced DNA double strand breaks, defective colony formation and cell death. Together, our results suggest that mutant KRAS promotes RAD51 expression to enhance DNA damage repair and lung cancer cell survival, suggesting that RAD51 may be an effective therapeutic target to overcome chemo/radioresistance in KRAS mutant cancers.

Keywords

References

  1. Blandin Knight S, Crosbie PA, Balata H, Chudziak J, Hussell T and Dive C (2017) Progress and prospects of early detection in lung cancer. Open Biol 7, 170070 https://doi.org/10.1098/rsob.170070
  2. Kaufman J and Stinchcombe TE (2017) Treatment of KRAS-Mutant Non-Small Cell Lung Cancer: The End of the Beginning for Targeted Therapies. JAMA 317, 1835-1837 https://doi.org/10.1001/jama.2017.3436
  3. Matikas A, Mistriotis D, Georgoulias V and Kotsakis A (2017) Targeting KRAS mutated non-small cell lung cancer: A history of failures and a future of hope for a diverse entity. Crit Rev Oncol Hematol 110, 1-12 https://doi.org/10.1016/j.critrevonc.2016.12.005
  4. Cox AD, Der CJ and Philips MR (2015) Targeting RAS membrane association: back to the future for anti-RAS drug discovery? Clin Cancer Res 21, 1819-1827 https://doi.org/10.1158/1078-0432.CCR-14-3214
  5. De Roock W, De Vriendt V, Normanno N, Ciardiello F and Tejpar S (2011) KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 12, 594-603 https://doi.org/10.1016/S1470-2045(10)70209-6
  6. Petermann E, Orta ML, Issaeva N, Schultz N and Helleday T (2010) Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Mol Cell 37, 492-502 https://doi.org/10.1016/j.molcel.2010.01.021
  7. Zafar F, Seidler SB, Kronenberg A, Schild D and Wiese C (2010) Homologous recombination contributes to the repair of DNA double-strand breaks induced by highenergy iron ions. Radiat Res 173, 27-39 https://doi.org/10.1667/RR1910.1
  8. Su F, Mukherjee S, Yang Y et al (2014) Nonenzymatic role for WRN in preserving nascent DNA strands after replication stress. Cell Rep 9, 1387-1401 https://doi.org/10.1016/j.celrep.2014.10.025
  9. Alshareeda AT, Negm OH, Aleskandarany MA et al (2016) Clinical and biological significance of RAD51 expression in breast cancer: a key DNA damage response protein. Breast Cancer Res Treat 159, 41-53 https://doi.org/10.1007/s10549-016-3915-8
  10. Nagathihalli NS and Nagaraju G (2011) RAD51 as a potential biomarker and therapeutic target for pancreatic cancer. Biochim Biophys Acta 1816, 209-218
  11. Maacke H, Jost K, Opitz S et al (2000) DNA repair and recombination factor Rad51 is over-expressed in human pancreatic adenocarcinoma. Oncogene 19, 2791-2795 https://doi.org/10.1038/sj.onc.1203578
  12. Balbous A, Cortes U, Guilloteau K et al (2016) A radiosensitizing effect of RAD51 inhibition in glioblastoma stem-like cells. BMC Cancer 16, 604 https://doi.org/10.1186/s12885-016-2647-9
  13. Kalimutho M, Bain AL, Mukherjee B et al (2017) Enhanced dependency of KRAS-mutant colorectal cancer cells on RAD51-dependent homologous recombination repair identified from genetic interactions in Saccharomyces cerevisiae. Mol Oncol 11, 470-490 https://doi.org/10.1002/1878-0261.12040
  14. Roman M, Baraibar I, Lopez I et al (2018) KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol Cancer 17, 33 https://doi.org/10.1186/s12943-018-0789-x
  15. Eder S, Arndt A, Lamkowski A et al (2017) Baseline MAPK signaling activity confers intrinsic radioresistance to KRAS-mutant colorectal carcinoma cells by rapid upregulation of heterogeneous nuclear ribonucleoprotein K (hnRNP K). Cancer Lett 385, 160-167 https://doi.org/10.1016/j.canlet.2016.10.027
  16. Eilers M and Eisenman RN (2008) Myc's broad reach. Genes Dev 22, 2755-2766 https://doi.org/10.1101/gad.1712408
  17. Ischenko I, Zhi J, Hayman MJ and Petrenko O (2017) KRAS-dependent suppression of MYC enhances the sensitivity of cancer cells to cytotoxic agents. Oncotarget 8, 17995-18009 https://doi.org/10.18632/oncotarget.14929
  18. Perera D and Venkitaraman AR (2016) Oncogenic KRAS triggers MAPK-dependent errors in mitosis and MYCdependent sensitivity to anti-mitotic agents. Sci Rep 6, 29741 https://doi.org/10.1038/srep29741
  19. Grabocka E, Commisso C and Bar-Sagi D (2015) Molecular pathways: targeting the dependence of mutant RAS cancers on the DNA damage response. Clin Cancer Res 21, 1243-1247 https://doi.org/10.1158/1078-0432.CCR-14-0650
  20. Dietlein F, Kalb B, Jokic M et al (2015) A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer. Cell 162, 146-159 https://doi.org/10.1016/j.cell.2015.05.053
  21. Zhao L, Pu X, Ye Y, Lu C, Chang JY and Wu X (2016) Association between genetic variants in DNA doublestrand break repair pathways and risk of radiation therapy-induced pneumonitis and esophagitis in nonsmall cell lung cancer. Cancers (Basel) 8, E23 https://doi.org/10.3390/cancers8020023
  22. Scarbrough PM, Weber RP, Iversen ES et al (2016) A cross-cancer genetic association analysis of the DNA repair and DNA damage signaling pathways for lung, ovary, prostate, breast, and colorectal cancer. Cancer Epidemiol Biomarkers Prev 25, 193-200 https://doi.org/10.1158/1055-9965.EPI-15-0649
  23. Rothschild SI, Gautschi O, Lara PN Jr, Mack PC and Gandara DR (2011) Biomarkers of DNA repair and related pathways: significance in non-small cell lung cancer. Curr Opin Oncol 23, 150-157 https://doi.org/10.1097/CCO.0b013e328341ee38
  24. O'Grady S, Finn SP, Cuffe S, Richard DJ, O'Byrne KJ and Barr MP (2014) The role of DNA repair pathways in cisplatin resistant lung cancer. Cancer Treat Rev 40, 1161-1170 https://doi.org/10.1016/j.ctrv.2014.10.003
  25. Chen P, Li J, Chen YC et al (2016) The functional status of DNA repair pathways determines the sensitization effect to cisplatin in non-small cell lung cancer cells. Cell Oncol (Dordr) 39, 511-522 https://doi.org/10.1007/s13402-016-0291-7
  26. Soucek L, Whitfield JR, Sodir NM et al (2013) Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev 27, 504-513 https://doi.org/10.1101/gad.205542.112
  27. Luoto KR, Meng AX, Wasylishen AR et al (2010) Tumor cell kill by c-MYC depletion: role of MYC-regulated genes that control DNA double-strand break repair. Cancer Res 70, 8748-8759 https://doi.org/10.1158/0008-5472.CAN-10-0944
  28. Tang Z, Li C, Kang B, Gao G, Li C and Zhang Z (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45, W98-W102 https://doi.org/10.1093/nar/gkx247