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Article

Camptothecin and cisplatin upregulate ABCG2 and MRP2 expression by activating the ATM/NF-κB pathway in lung cancer cells

  • Authors:
    • Shi Zhong Ke
    • Xiao Yan Ni
    • Yue Hua Zhang
    • Yi Nan Wang
    • Bin Wu
    • Feng Guang Gao
  • View Affiliations / Copyright

    Affiliations: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen 361005, P.R. China, Department of Pharmacology, Affiliated Renji Hospital of Shanghai Jiao Tong University, Shanghai 200030, P.R. China
  • Pages: 1289-1296
    |
    Published online on: February 1, 2013
       https://doi.org/10.3892/ijo.2013.1805
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Abstract

Multidrug resistance (MDR) formation is an important problem in lung cancer chemotherapy. Our study showed that both camptothecin and cisplatin could not only induce ATM and NF-κB activation but also upregulate expression of the MDR-related genes ABCG2, MRP2 in NCI-H446 cells. Moreover, camptothecin and cisplatin-induced ABCG2 and MRP2 upregulation could be impaired by ATM and NF-κB inhibitors, indicating a relationship between ATM, NF-κB activation and MDR formation in lung cancer chemo­therapy. Our study indicates that ATM may serve as a potential mole­cular target for MDR formation in lung cancer chemotherapy.
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1 

Tan XL, Moyer AM, Fridley BL, et al: Genetic variation predicting cisplatin cytotoxicity associated with overall survival in lung cancer patients receiving platinum-based chemotherapy. Clin Cancer Res. 17:5801–5811. 2011. View Article : Google Scholar

2 

Shinoda C, Maruyama M, Fujishita T, et al: Doxorubicin induces expression of multidrug resistance-associated protein 1 in human small cell lung cancer cell lines by the c-jun N-terminal kinase pathway. Int J Cancer. 117:21–31. 2005. View Article : Google Scholar

3 

Spiro SG, Tanner NT, Silvestri GA, et al: Lung cancer: progress in diagnosis, staging and therapy. Respirology. 15:44–50. 2010. View Article : Google Scholar : PubMed/NCBI

4 

Yamazaki R, Nishiyama Y, Furuta T, et al: Novel acrylonitrile derivatives, YHO-13177 and YHO-13351, reverse BCRP/ABCG2-mediated drug resistance in vitro and in vivo. Mol Cancer Ther. 10:1252–1263. 2011. View Article : Google Scholar : PubMed/NCBI

5 

Kim DH, Sriharsha L, Xu W, et al: Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res. 15:4750–4758. 2009. View Article : Google Scholar

6 

Doyle LA and Ross DD: Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene. 22:7340–7358. 2003. View Article : Google Scholar : PubMed/NCBI

7 

Robey RW, Medina-Pérez WY, Nishiyama K, et al: Over-expression of the ATP-binding cassette half-transporter, ABCG2 (Mxr/BCrp/ABCP1), in flavopiridol-resistant human breast cancer cells. Clin Cancer Res. 7:145–152. 2001.PubMed/NCBI

8 

Candeil L, Gourdier I, Peyron D, et al: ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan-treated metastases. Int J Cancer. 109:848–854. 2004. View Article : Google Scholar : PubMed/NCBI

9 

Diestra JE, Scheffer GL, Catala I, et al: Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material. J Pathol. 198:213–219. 2002. View Article : Google Scholar

10 

Turne JG, Gump JL, Zhang C, et al: ABCG2 expression, function and promoter methylation in human multiple myeloma. Blood. 108:3881–3889. 2006. View Article : Google Scholar : PubMed/NCBI

11 

Yamasaki M, Makino T, Masuzawa T, et al: Role of multidrug resistance protein 2 (MRP2) in chemoresistance and clinical outcome in oesophageal squamous cell carcinoma. Br J Cancer. 104:707–713. 2011. View Article : Google Scholar : PubMed/NCBI

12 

Chen ZS and Tiwari AK: Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases. FEBS J. 278:3226–3245. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Spanswick VJ, Lowe HL, Newton C, et al: Evidence for different mechanisms of ‘unhooking’ for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples. BMC Cancer. 12:4362012.

14 

Gaudio E, Spizzo R, Paduano F, et al: Tcl1 interacts with ATM and enhances NF-κB activation in hematologic malignancies. Blood. 119:180–187. 2012.PubMed/NCBI

15 

Svirnovski AI, Serhiyenka TF, Kustanovich AM, Khlebko PV, Fedosenko VV, Taras IB and Bakun AV: DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells. Exp Oncol. 32:258–262. 2010.PubMed/NCBI

16 

Bae JB, Mukhopadhyay SS, Liu L, et al: Snm1B/Apollo mediates replication fork collapse and S Phase checkpoint activation in response to DNA interstrand cross-links. Oncogene. 27:5045–5056. 2008. View Article : Google Scholar : PubMed/NCBI

17 

Bakkenist CJ and Kastan MB: DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 421:499–506. 2003. View Article : Google Scholar : PubMed/NCBI

18 

Karin M and Greten FR: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 5:749–759. 2005. View Article : Google Scholar : PubMed/NCBI

19 

Lin Y, Bai L, Chen W and Xu S: The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opin Ther Targets. 14:45–55. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Campbell KJ, O’Shea JM and Perkins ND: Differential regulation of NF-kappaB activation and function by topoisomerase II inhibitors. BMC Cancer. 6:1012006. View Article : Google Scholar : PubMed/NCBI

21 

Melisi D and Chiao PJ: NF-kappa B as a target for cancer therapy. Expert Opin Ther Targets. 11:133–144. 2007. View Article : Google Scholar : PubMed/NCBI

22 

Konstantinopoulos PA, Fountzilas E, Pillay K, et al: Carboplatin-induced gene expression changes in vitro are prognostic of survival in epithelial ovarian cancer. BMC Med Genomics. 1:592008. View Article : Google Scholar : PubMed/NCBI

23 

Wu ZH, Shi Y, Tibbetts RS and Miyamoto S: Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Science. 311:1141–1146. 2006. View Article : Google Scholar : PubMed/NCBI

24 

Hu SX, Sui HX, Jin HJ, et al: Lipopolysaccharide and dose of nicotine determine the effects of nicotine on murine bone marrow-derived dendritic cells. Mol Med Rep. 5:1005–1010. 2012.PubMed/NCBI

25 

Zhang L and Yu H: Neuroprotective effects of salidroside against beta-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Neurochem Int. 57:547–555. 2010. View Article : Google Scholar

26 

Buhrmann C, Mobasheri A, Busch F, Aldinger C, Stahlmann R, Montaseri A and Shakibaei M: Curcumin modulates nuclear factor kappaB (NF-kappaB)-mediated inflammation in human tenocytes in vitro: role of the phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem. 286:28556–28566. 2011. View Article : Google Scholar

27 

Dioum EM, Osborne JK, Goetsch S, Russell J, Schneider JW and Cobb MH: A small molecule differentiation inducer increases insulin production by pancreatic β cells. Proc Natl Acad Sci USA. 108:20713–20718. 2011.PubMed/NCBI

28 

Jin HJ, Li HT, Sui HX, Xue MQ, Wang YN, Wang JX and Gao FG: Nicotine stimulated bone marrow-derived dendritic cells could augment HBV specific CTL priming by activating PI3K-Akt pathway. Immunol Lett. 146:40–49. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Heo JI, Oh SJ, Kho, et al: ATM mediates interdependent activation of p53 and ERK through formation of a ternary complex with p-p53 and p-ERK in response to DNA damage. Mol Biol Rep. 39:8007–8014. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Ai L, Skehan RR, Saydi J, Lin T and Brown KD: Ataxia-telangiectasia, mutated (ATM)/nuclear factor κ light chain enhancer of activated B cells (NF-κB) signaling controls basal and DNA damage-induced transglutaminase 2 expression. J Biol Chem. 287:18330–18341. 2012.

31 

Togashi H, Sasaki M, Frohman E, et al: Neuronal (type I) nitric oxide synthase regulates nuclear factor κB activity and immunologic (type II) nitric oxide synthase expression. Proc Natl Acad Sci USA. 94:2676–2680. 1997.

32 

Tenopoulou M, Kurz T, Doulias PT, Galaris D and Brunk UT: Does the calcein-AM method assay the total cellular ‘labile iron pool’ or only a fraction of it? Biochem J. 403:261–266. 2007.

33 

Zolner AE, Abdou I, Ye R, et al: Phosphorylation of polynucleotide kinase/phosphatase by DNA-dependent protein kinase and ataxia-telangiectasia mutated regulates its association with sites of DNA damage. Nucleic Acids Res. 39:9224–9237. 2011. View Article : Google Scholar

34 

Alexande A, Cai SL, Kim J, et al: ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci USA. 107:4153–4158. 2010. View Article : Google Scholar : PubMed/NCBI

35 

Korita PV, Wakai T, Shirai Y, et al: Multidrug resistance associated protein 2 determines the efficacy of cisplatin in patients with hepatocellular carcinoma. Oncol Rep. 23:965–972. 2010.PubMed/NCBI

36 

Yasui K, Mihara S, Zhao C, et al: Alteration in copy numbers of genes as a mechanism for acquired drug resistance. Cancer Res. 64:1403–1410. 2004. View Article : Google Scholar : PubMed/NCBI

37 

Cho S, Lu M, He X, Ee PL, Bhat U, Schneider E, Miele L and Beck WT: Notch1 regulates the expression of the multidrug resistance gene ABCC1/MRP1 in cultured cancer cells. Proc Natl Acad Sci USA. 108:20778–20783. 2011. View Article : Google Scholar : PubMed/NCBI

38 

Bram EE, Stark M, Raz S and Assaraf YG: Chemotherapeutic drug-induced ABCG2 promoter demethylation as a novel mechanism of acquired multidrug resistance. Neoplasia. 11:1359–1370. 2009.PubMed/NCBI

39 

Yang Y, Xia F, Hermance N, et al: A cytosolic ATM/NEMO/RIP1 complex recruits TAK1 to mediate the NF-kappaB and p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 responses to DNA damage. Mol Cell Biol. 31:2774–2786. 2011. View Article : Google Scholar : PubMed/NCBI

40 

Miyamoto S: Nuclear initiated NF-κB signaling: NEMO and ATM take center stage. Cell Res. 21:116–130. 2011.

41 

Wu ZH and Miyamoto S: Induction of a pro-apoptotic ATM-NF-κB pathway and its repression by ATR in response to replication stress. EMBO J. 27:1963–1973. 2008.

42 

Ling J, Kang Y, Zhao R, et al: KrasG12D-induced IKK2/β/NF-ϰB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell. 21:105–120. 2012.

43 

Li F and Sethi G: Targeting transcription factor NF-κB to overcome chemoresistance and radioresistance in cancer therapy. Biochim Biophys Acta. 1805:167–180. 2010.

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Copy and paste a formatted citation
Spandidos Publications style
Ke SZ, Ni XY, Zhang YH, Wang YN, Wu B and Gao FG: Camptothecin and cisplatin upregulate ABCG2 and MRP2 expression by activating the ATM/NF-κB pathway in lung cancer cells. Int J Oncol 42: 1289-1296, 2013.
APA
Ke, S.Z., Ni, X.Y., Zhang, Y.H., Wang, Y.N., Wu, B., & Gao, F.G. (2013). Camptothecin and cisplatin upregulate ABCG2 and MRP2 expression by activating the ATM/NF-κB pathway in lung cancer cells. International Journal of Oncology, 42, 1289-1296. https://doi.org/10.3892/ijo.2013.1805
MLA
Ke, S. Z., Ni, X. Y., Zhang, Y. H., Wang, Y. N., Wu, B., Gao, F. G."Camptothecin and cisplatin upregulate ABCG2 and MRP2 expression by activating the ATM/NF-κB pathway in lung cancer cells". International Journal of Oncology 42.4 (2013): 1289-1296.
Chicago
Ke, S. Z., Ni, X. Y., Zhang, Y. H., Wang, Y. N., Wu, B., Gao, F. G."Camptothecin and cisplatin upregulate ABCG2 and MRP2 expression by activating the ATM/NF-κB pathway in lung cancer cells". International Journal of Oncology 42, no. 4 (2013): 1289-1296. https://doi.org/10.3892/ijo.2013.1805
Copy and paste a formatted citation
x
Spandidos Publications style
Ke SZ, Ni XY, Zhang YH, Wang YN, Wu B and Gao FG: Camptothecin and cisplatin upregulate ABCG2 and MRP2 expression by activating the ATM/NF-κB pathway in lung cancer cells. Int J Oncol 42: 1289-1296, 2013.
APA
Ke, S.Z., Ni, X.Y., Zhang, Y.H., Wang, Y.N., Wu, B., & Gao, F.G. (2013). Camptothecin and cisplatin upregulate ABCG2 and MRP2 expression by activating the ATM/NF-κB pathway in lung cancer cells. International Journal of Oncology, 42, 1289-1296. https://doi.org/10.3892/ijo.2013.1805
MLA
Ke, S. Z., Ni, X. Y., Zhang, Y. H., Wang, Y. N., Wu, B., Gao, F. G."Camptothecin and cisplatin upregulate ABCG2 and MRP2 expression by activating the ATM/NF-κB pathway in lung cancer cells". International Journal of Oncology 42.4 (2013): 1289-1296.
Chicago
Ke, S. Z., Ni, X. Y., Zhang, Y. H., Wang, Y. N., Wu, B., Gao, F. G."Camptothecin and cisplatin upregulate ABCG2 and MRP2 expression by activating the ATM/NF-κB pathway in lung cancer cells". International Journal of Oncology 42, no. 4 (2013): 1289-1296. https://doi.org/10.3892/ijo.2013.1805
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