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Tumor Biology

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01.12.2015 | Research Article

Targeting DNA-PKcs increased anticancer drug sensitivity by suppressing DNA damage repair in osteosarcoma cell line MG63

verfasst von: Xin Li, Jiguang Tian, Qiyu Bo, Ka Li, Hongliang Wang, Ting Liu, Jianmin Li

Erschienen in: Tumor Biology | Ausgabe 12/2015

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Abstract

Many chemotherapy drugs exert anticancer effects through causing DNA damage, such as DNA topoisomerase inhibitor and platinum-containing drugs. DNA damage repair is an important mechanism of drug resistance which is responsible for metastasis and recurrence after chemotherapy. DNA-dependent protein kinase (DNA-PK) plays an important role in non-homology end joining (NHEJ) pathway. In this study, we aimed to determine whether DNA-PK catalytic subunit (DNA-PKcs) is expressed in osteosarcoma MG63 cell line and involved in drug resistance induced by DNA repair. We found that DNA-PKcs was expressed in osteosarcoma cell line MG63. The pDNA-PKcs^T2609 was more expressed in cells treated with cisplatin (DDP) and etoposide (VP16). Down-regulation of DNA-PKcs produced higher sensitivity of MG63 cells to DDP or VP16 through increasing apoptosis and causing cell cycle arrest in the G1 phase. Our study supported that DNA-PKcs was involved in drug-induced DNA damage repair and related to chemosensitivity of osteosarcoma MG63 cells.

Meyers PA. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. Expert Rev Anticancer Ther. 2009;9:1035–49.CrossRefPubMed

Jackson SP. DNA-dependent protein kinase. Int J Biochem Cell Biol. 1997;29:935–8.CrossRefPubMed

Mi J, Dziegielewski J, Bolesta E, Brautigan DL, Larner JM. Activation of DNA-PK by ionizing radiation is mediated by protein phosphatase 6. PLoS One. 2009;4:e4395.CrossRefPubMedPubMedCentral

Hosoi Y, Miyachi H, Matsumoto Y, Ikehata H, Komura J, Ishii K, et al. A phosphatidylinositol 3-kinase inhibitor wortmannin induces radioresistant DNA synthesis and sensitizes cells to bleomycin and ionizing radiation. Int J Cancer. 1998;78:642–7.CrossRefPubMed

Belenkov AI, Paiement JP, Panasci LC, Monia BP, Chow TY. An antisense oligonucleotide targeted to human Ku86 messenger RNA sensitizes M059K malignant glioma cells to ionizing radiation, bleomycin, and etoposide but not DNA cross-linking agents. Cancer Res. 2002;62:5888–96.PubMed

Shintani S, Mihara M, Li C, Nakahara Y, Hino S, Nakashiro K, et al. Up-regulation of DNA-dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma. Cancer Sci. 2003;94:894–900.CrossRefPubMed

Meyers PA, Healey JH, Chou AJ, Wexler LH, Merola PR, Morris CD, et al. Addition of pamidronate to chemotherapy for the treatment of osteosarcoma. Cancer. 2011;117:1736–44.CrossRefPubMed

Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3–13.CrossRefPubMed

Lieber MR. The mechanism of human nonhomologous DNA end joining. J Biol Chem. 2008;283:1–5.CrossRefPubMed

10.

Sengupta S, Harris CC. p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol. 2005;6:44–55.CrossRefPubMed

11.

Lieber MR. NHEJ and its backup pathways in chromosomal translocations. Nat Struct Mol Biol. 2010;17:393–5.CrossRefPubMedPubMedCentral

12.

Noguchi T, Shibata T, Fumoto S, Uchida Y, Mueller W, Takeno S. DNA-PKcs expression in esophageal cancer as a predictor for chemoradiation therapeutic sensitivity. Ann Surg Oncol. 2002;9:1017–22.CrossRefPubMed

13.

Zhao HJ, Hosoi Y, Miyachi H, Ishii K, Yoshida M, Nemoto K, et al. DNA-dependent protein kinase activity correlates with Ku70 expression and radiation sensitivity in esophageal cancer cell lines. Clin Cancer Res. 2000;6:1073–8.PubMed

14.

Beskow C, Skikuniene J, Holgersson A, Nilsson B, Lewensohn R, Kanter L, et al. Radioresistant cervical cancer shows upregulation of the NHEJ proteins DNA-PKcs, Ku70 and Ku86. Br J Cancer. 2009;101:816–21.CrossRefPubMedPubMedCentral

15.

Zhuang L, Yu SY, Huang XY, Cao Y, Xiong HH. Potentials of DNA-PKcs, Ku80, and ATM in enhancing radiosensitivity of cervical carcinoma cells. Ai Zheng. 2007;26:724–9.PubMed

16.

Soderlund Leifler K, Queseth S, Fornander T, Askmalm MS. Low expression of Ku70/80, but high expression of DNA-PKcs, predict good response to radiotherapy in early breast cancer. Int J Oncol. 2010;37:1547–54.PubMed

17.

Auckley DH, Crowell RE, Heaphy ER, Stidley CA, Lechner JF, Gilliland FD, et al. Reduced DNA-dependent protein kinase activity is associated with lung cancer. Carcinogenesis. 2001;22:723–7.CrossRefPubMed

18.

Sirzen F, Nilsson A, Zhivotovsky B, Lewensohn R. DNA-dependent protein kinase content and activity in lung carcinoma cell lines: correlation with intrinsic radiosensitivity. Eur J Cancer. 1999;35:111–6.CrossRefPubMed

19.

Yan SS, Liu L, Liu ZG, Zeng MS, Song LB, Xia YF. Expression and clinical significance of DNA-PKcs in nasopharyngeal carcinoma. Ai Zheng. 2008;27:979–83.PubMed

20.

Lee SW, Cho KJ, Park JH, Kim SY, Nam SY, Lee BJ, et al. Expressions of Ku70 and DNA-PKcs as prognostic indicators of local control in nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2005;62:1451–7.CrossRefPubMed

21.

Hande KR. Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer. 1998;34:1514–21.CrossRefPubMed

22.

Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol. 2010;17:421–33.CrossRefPubMed

23.

Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol. 2000;10:886–95.CrossRefPubMed

24.

Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273:5858–68.CrossRefPubMed

25.

MacPhail SH, Banath JP, Yu TY, Chu EH, Lambur H, Olive PL. Expression of phosphorylated histone H2AX in cultured cell lines following exposure to X-rays. Int J Radiat Biol. 2003;79:351–8.CrossRefPubMed

26.

Muller C, Christodoulopoulos G, Salles B, Panasci L. DNA-dependent protein kinase activity correlates with clinical and in vitro sensitivity of chronic lymphocytic leukemia lymphocytes to nitrogen mustards. Blood. 1998;92:2213–9.PubMed

27.

Muller C, Salles B. Regulation of DNA-dependent protein kinase activity in leukemic cells. Oncogene. 1997;15:2343–8.CrossRefPubMed

28.

Ciszewski WM, Tavecchio M, Dastych J. Curtin NJ.DNA-PK inhibition by NU7441 sensitizes breast cancer cells to ionizing radiation and doxorubicin. Breast Cancer Res Treat. 2014;143:47–55.CrossRefPubMed

29.

Halazonetis TD, Gorgoulis VG, Bartek J. An oncogene-induced DNA damage model for cancer development. Science. 2008;319:1352–5.CrossRefPubMed

30.

Rengarajan T, Rajendran P, Nandakumar N, Balasubramanian MP, Nishigaki I. Cancer preventive efficacy of marine carotenoid fucoxanthin: cell cycle arrest and apoptosis. Nutrients. 2013;5:4978–89.CrossRefPubMedPubMedCentral

31.

Garcia-Cao I, Duran A, Collado M, Carrascosa MJ, Martin-Caballero J, Flores JM, et al. Tumour-suppression activity of the proapoptotic regulator Par4. EMBO Rep. 2005;6:577–83.CrossRefPubMedPubMedCentral

32.

Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature. 2005;436:660–5.CrossRefPubMed

33.

Tian X, Chen G, Xing H, Weng D, Guo Y, Ma D. The relationship between the down-regulation of DNA-PKcs or Ku70 and the chemosensitization in human cervical carcinoma cell line HeLa. Oncol Rep. 2007;18:927–32.PubMed

34.

Friesen C, Uhl M, Pannicke U, Schwarz K, Miltner E, Debatin KM. DNA-ligase IV and DNA-protein kinase play a critical role in deficient caspases activation in apoptosis-resistant cancer cells by using doxorubicin. Mol Biol Cell. 2008;19:3283–9.CrossRefPubMedPubMedCentral

Titel: Targeting DNA-PKcs increased anticancer drug sensitivity by suppressing DNA damage repair in osteosarcoma cell line MG63
verfasst von: Xin Li
Jiguang Tian
Qiyu Bo
Ka Li
Hongliang Wang
Ting Liu
Jianmin Li
Publikationsdatum: 01.12.2015
Verlag: Springer Netherlands
Erschienen in: Tumor Biology / Ausgabe 12/2015
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-015-3642-5

Springer Medizin

Targeting DNA-PKcs increased anticancer drug sensitivity by suppressing DNA damage repair in osteosarcoma cell line MG63

Abstract

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Springer Medizin

Abstract

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