Open Access

Quinalizarin, a specific CK2 inhibitor, can reduce icotinib resistance in human lung adenocarcinoma cell lines

  • Authors:
    • Ke Li
    • Fangzheng Zhou
    • Yu Zhou
    • Sheng Zhang
    • Qianwen Li
    • Zhenyu Li
    • Li Liu
    • Gang Wu
    • Rui Meng
  • View Affiliations

  • Published online on: May 30, 2019     https://doi.org/10.3892/ijmm.2019.4220
  • Pages: 437-446
  • Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The abnormal activation of the downstream signaling pathways of epidermal growth factor receptor (EGFR) that are independent of EGFR, contribute to the acquisition of EGFR‑tyrosine kinase inhibitor (TKI) resistance in non‑small cell lung cancer (NSCLC). The serine/threonine protein kinase casein kinase II (CK2) phosphorylates and modulates several members of the EGFR downstream signaling pathways. Thus, the purpose of the current study was to investigate the effects of the addition of quinalizarin (a specific CK2 inhibitor) to icotinib (an EGFR‑TKI) on the proliferation and apoptosis of four NSCLC cell lines and its underlying mechanisms. The human lung adenocarcinoma cell lines HCC827, A549, H1650 and H1975 were employed to represent the EGFR‑TKI‑sensitive EGFR (EGFR‑sensitive) mutation, wild‑type EGFR and the EGFR‑TKI‑resistant EGFR (EGFR‑resistant) mutations. The cell viability was determined by the MTT assay. Cell apoptosis was detected by flow cytometry using the Annexin V‑enhanced green fluorescent protein Apoptosis Detection kit. The level of proteins in the EGFR downstream pathway was observed using a western blot assay. The results showed that the cells with the EGFR‑sensitive mutation (HCC827, EGFR E716‑A750del) were more sensitive to icotinib compared with those possessing the EGFR wild‑type (A549) and the EGFR‑resistant mutations (H1650, EGFR E716‑A750del and PTEN lost; H1975, EGFR L858R+T790M). Quinalizarin inhibited proliferation and promoted apoptosis in the cells with the EGFR wild‑type and resistant mutations, and the addition of quinalizarin to icotinib partially restored their sensitivity to icotinib. Quinalizarin and/or icotinib increased the apoptotic rates in the EGFR‑TKI resistant cells, and the combination of these reduced the level of protein downstream of EGFR, including phosphorylated (p‑AKT) and p‑(ERK). In conclusion, quinalizarin may partially sensitize cells to icotinib by inhibiting proliferation and promoting apoptosis mediated by AKT and ERK in EGFR‑TKI resistant NSCLC cell lines.

References

1 

Bareschino MA, Schettino C, Rossi A, Maione P, Sacco PC, Zeppa R and Gridelli C: Treatment of advanced non small cell lung cancer. J Thorac Dis. 3:122–133. 2011.

2 

Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, Heeroma K, Itoh Y, Cornelio G and Yang PC: A prospective, molecular epidemiology study of EGFR mutations in asian patients with advanced non-small-cell lung cancer of adeno-carcinoma histology (PIONEER). J Thorac Oncol. 9:154–162. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Wu YL, Chu DT, Han B, Liu X, Zhang L, Zhou C, Liao M, Mok T, Jiang H, Duffield E and Fukuoka M: Phase III, randomized, open-label, first-line study in asia of gefitinib versus carbo-platin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer: Evaluation of patients recruited from mainland China. Asia-Pac J Clin Oncol. 8:232–243. 2012. View Article : Google Scholar

4 

Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 361:947–957. 2009. View Article : Google Scholar : PubMed/NCBI

5 

Thongprasert S, Duffield E, Saijo N, Wu YL, Yang JC, Chu DT, Liao M, Chen YM, Kuo HP, Negoro S, et al: Health-related quality-of-life in a randomized phase III first-line study of gefi-tinib versus carboplatin/paclitaxel in clinically selected patients from Asia with advanced NSCLC (IPASS). J Thorac Oncol. 6:1872–1880. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Ellis PM, Coakley N, Feld R, Kuruvilla S and Ung YC: Use of the epidermal growth factor receptor inhibitors gefitinib, erlotinib, afatinib, dacomitinib, and icotinib in the treatment of non-small-cell lung cancer: A systematic review. Curr Oncol. 22:e183–e215. 2015. View Article : Google Scholar : PubMed/NCBI

7 

Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA, Lynch T, Johnson BE and Miller VA: Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 28:357–360. 2010. View Article : Google Scholar

8 

Gao Z, Chen W, Zhang X, Cai P, Fang X, Xu Q, Sun Y and Gu Y: Icotinib, a potent and specific EGFR tyrosine kinase inhibitor, inhibits growth of squamous cell carcinoma cell line A431 through negatively regulating AKT signaling. Biomed Pharmacother. 67:351–356. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Chen X, Zhu Q, Liu Y, Liu P, Yin Y, Guo R, Lu K, Gu Y, Liu L, Wang J, et al: Icotinib is an active treatment of non-small-cell lung cancer: A retrospective study. PLoS One. 9:e958972014. View Article : Google Scholar : PubMed/NCBI

10 

Liang W, Wu X, Fang W, Zhao Y, Yang Y, Hu Z, Xue C, Zhang J, Zhang J, Ma Y, et al: Network meta-analysis of erlotinib, gefitinib, afatinib and icotinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations. PLoS One. 9:e852452014. View Article : Google Scholar : PubMed/NCBI

11 

Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, Wang D, Li Q, Qin S, Hu C, et al: Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): A randomised, double-blind phase 3 non-inferiority trial. Lancet Oncol. 14:953–961. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Antonicelli A, Cafarotti S, Indini A, Galli A, Russo A, Cesario A, Lococo FM, Russo P, Mainini AF, Bonifati LG, et al: EGFR-targeted therapy for non-small cell lung cancer: Focus on EGFR oncogenic mutation. Int J Med Sci. 10:320–330. 2013. View Article : Google Scholar : PubMed/NCBI

13 

Zhou C and Yao LD: Strategies to improve outcomes of patients with EGRF-mutant non-small cell lung cancer: Review of the literature. J Thorac Oncol. 11:174–186. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M and Eck MJ: The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA. 105:2070–2075. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, et al: Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 3:75ra262011. View Article : Google Scholar : PubMed/NCBI

16 

Meggio F and Pinna LA: One-thousand-and-one substrates of protein kinase CK2? FASEB J. 17:349–368. 2003. View Article : Google Scholar : PubMed/NCBI

17 

Ortega CE, Seidner Y and Dominguez I: Mining CK2 in cancer. PLoS One. 9:e1156092014. View Article : Google Scholar : PubMed/NCBI

18 

Torres J and Pulido R: The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. implications for PTEN stability to proteasome-mediated degradation. J Biol Chem. 276:993–998. 2001. View Article : Google Scholar

19 

Cozza G, Mazzorana M, Papinutto E, Bain J, Elliott M, di Maira G, Gianoncelli A, Pagano MA, Sarno S, Ruzzene M, et al: Quinalizarin as a potent, selective and cell-permeable inhibitor of protein kinase CK2. Biochem J. 421:387–395. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Daya-Makin M, Sanghera JS, Mogentale TL, Lipp M, Parchomchuk J, Hogg JC and Pelech SL: Activation of a tumor-associated protein kinase (p40TAK) and casein kinase 2 in human squamous cell carcinomas and adenocarcinomas of the lung. Cancer Res. 54:2262–2268. 1994.PubMed/NCBI

21 

Faust M, Schuster N and Montenarh M: Specific binding of protein kinase CK2 catalytic subunits to tubulin. FEBS Lett. 462:51–56. 1999. View Article : Google Scholar : PubMed/NCBI

22 

Lee CK, Kim S, Lee JS, Lee JE, Kim SM, Yang IS, Kim HR, Lee JH, Kim S and Cho B: Next-generation sequencing reveals novel resistance mechanisms and molecular heterogeneity in EGFR-mutant non-small cell lung cancer with acquired resistance to EGFR-TKIs. Lung Cancer. 113:106–114. 2017. View Article : Google Scholar : PubMed/NCBI

23 

Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, et al: AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 4:1046–1061. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Di Maira G, Salvi M, Arrigoni G, Marin O, Sarno S, Brustolon F, Pinna LA and Ruzzene M: Protein kinase CK2 phosphorylates and upregulates Akt/PKB. Cell Death Differ. 12:668–677. 2005. View Article : Google Scholar : PubMed/NCBI

25 

Duncan JS and Litchfield DW: Too much of a good thing: The role of protein kinase CK2 in tumorigenesis and prospects for therapeutic inhibition of CK2. Biochim Biophys Acta. 1784:33–47. 2008. View Article : Google Scholar

26 

Hay N: Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta. 1813:1965–1970. 2011. View Article : Google Scholar : PubMed/NCBI

27 

Wu SG and Shih JY: Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer. 17:382018. View Article : Google Scholar : PubMed/NCBI

28 

Chua MM, Ortega CE, Sheikh A, Lee M, Abdul-Rassoul H, Hartshorn KL and Dominguez I: CK2 in cancer: Cellular and biochemical mechanisms and potential therapeutic target. Pharmaceuticals (Basel). 10. pp. E182017, View Article : Google Scholar

29 

Yaylim I and Isbir T: Enhanced casein kinase II (CK II) activity in human lung tumours. Anticancer Res. 22:215–218. 2002.PubMed/NCBI

30 

Hung MS, Xu Z, Chen Y, Smith E, Mao JH, Hsieh D, Lin YC, Yang CT, Jablons DM and You L: Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model. Int j Oncol. 43:1517–1522. 2013. View Article : Google Scholar : PubMed/NCBI

31 

Li Q, Li K, Yang T, Zhang S, Zhou Y, Li Z, Xiong J, Zhou F, Zhou X, Liu L, et al: Association of protein kinase CK2 inhibition with cellular radiosensitivity of non-small cell lung cancer. Sci Rep. 7:161342017. View Article : Google Scholar : PubMed/NCBI

32 

Kim J and Kim SH: Druggability of the CK2 inhibitor CX-4945 as an anticancer drug and beyond. Arch Pharm Res. 35:1293–1296. 2012. View Article : Google Scholar : PubMed/NCBI

33 

Ku MJ, Park JW, Ryu BJ, Son YJ, Kim SH and Lee SY: CK2 inhibitor CX4945 induces sequential inactivation of proteins in the signaling pathways related with cell migration and suppresses metastasis of A549 human lung cancer cells. Bioorg Med Chem Lett. 23:5609–5613. 2013. View Article : Google Scholar : PubMed/NCBI

34 

Di Maira G, Brustolon F, Bertacchini J, Tosoni K, Marmiroli S, Pinna LA and Ruzzene M: Pharmacological inhibition of protein kinase CK2 reverts the multidrug resistance phenotype of a CEM cell line characterized by high CK2 level. Oncogene. 26:6915–6926. 2007. View Article : Google Scholar : PubMed/NCBI

35 

Asati V, Mahapatra DK and Bharti SK: PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur J Med Chem. 109:314–341. 2016. View Article : Google Scholar : PubMed/NCBI

36 

Lieber M, Smith B, Szakal A, Nelson-Rees W and Todaro G: A continuous tumor-cell line from a human lung carcinoma with properties of type II alveolar epithelial cells. Int J Cancer. 17:62–70. 1976. View Article : Google Scholar : PubMed/NCBI

37 

Greve G, Schiffmann I, Pfeifer D, Pantic M, Schuler J and Lubbert M: The pan-HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR-mutated and -wildtype non-small cell lung cancer cells. BMC Cancer. 15:9472015. View Article : Google Scholar : PubMed/NCBI

38 

Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R, Zander T, Seeger JM, Weiss J, Fischer F, Frommolt P, et al: PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res. 69:3256–3261. 2009. View Article : Google Scholar : PubMed/NCBI

39 

Ritt DA, Zhou M, Conrads TP, Veenstra TD, Copeland TD and Morrison DK: CK2 is a component of the KSR1 scaffold complex that contributes to raf kinase activation. Curr Biol. 17:179–184. 2007. View Article : Google Scholar

40 

Parker R, Clifton-Bligh R and Molloy MP: Phosphoproteomics of MAPK inhibition in BRAF-mutated cells and a role for the lethal synergism of dual BRAF and CK2 inhibition. Mol Cancer Ther. 13:1894–1906. 2014. View Article : Google Scholar : PubMed/NCBI

41 

So KS, Rho JK, Choi YJ, Kim SY, Choi CM, Chun YJ and Lee JC: AKT/mTOR down-regulation by CX-4945, a CK2 inhibitor, promotes apoptosis in chemorefractory non-small cell lung cancer cells. Anticancer Res. 35:1537–1542. 2015.PubMed/NCBI

42 

Yip PY: Phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway in non-small cell lung cancer. Transl Lung Cancer Res. 4:165–176. 2015.PubMed/NCBI

43 

Reungwetwattana T and Dy GK: Targeted therapies in development for non-small cell lung cancer. J Carcinog. 12:222013. View Article : Google Scholar

44 

Zer A and Leighl N: Promising targets and current clinical trials in metastatic non-squamous NSCLC. Front Oncol. 4:3292014. View Article : Google Scholar : PubMed/NCBI

45 

Bliesath J, Huser N, Omori M, Bunag D, Proffitt C, Streiner N, Ho C, Siddiqui-Jain A, O'Brien SE, Lim JK, et al: Combined inhibition of EGFR and CK2 augments the attenuation of PI3K-Akt-mTOR signaling and the killing of cancer cells. Cancer Lett. 322:113–118. 2012. View Article : Google Scholar : PubMed/NCBI

46 

So KS, Kim CH, Rho JK, Kim SY, Choi YJ, Song JS, Kim WS, Choi CM, Chun YJ and Lee JC: Autophagosome-mediated EGFR down-regulation induced by the CK2 inhibitor enhances the efficacy of EGFR-TKI on EGFR-mutant lung cancer cells with resistance by T790M. PLoS One. 9:e1140002014. View Article : Google Scholar : PubMed/NCBI

47 

Ke EE and Wu YL: EGFR as a pharmacological target in EGFR-mutant non-small-cell lung cancer: Where do we stand now? Trends Pharmacol Sci. 37:887–903. 2016. View Article : Google Scholar : PubMed/NCBI

48 

Morgillo F, Della Corte CM, Fasano M and Ciardiello F: Mechanisms of resistance to EGFR-targeted drugs: Lung cancer. ESMO Open. 1:e0000602016. View Article : Google Scholar : PubMed/NCBI

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August 2019
Volume 44 Issue 2

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Copy and paste a formatted citation
APA
Li, K., Zhou, F., Zhou, Y., Zhang, S., Li, Q., Li, Z. ... Meng, R. (2019). Quinalizarin, a specific CK2 inhibitor, can reduce icotinib resistance in human lung adenocarcinoma cell lines. International Journal of Molecular Medicine, 44, 437-446. https://doi.org/10.3892/ijmm.2019.4220
MLA
Li, K., Zhou, F., Zhou, Y., Zhang, S., Li, Q., Li, Z., Liu, L., Wu, G., Meng, R."Quinalizarin, a specific CK2 inhibitor, can reduce icotinib resistance in human lung adenocarcinoma cell lines". International Journal of Molecular Medicine 44.2 (2019): 437-446.
Chicago
Li, K., Zhou, F., Zhou, Y., Zhang, S., Li, Q., Li, Z., Liu, L., Wu, G., Meng, R."Quinalizarin, a specific CK2 inhibitor, can reduce icotinib resistance in human lung adenocarcinoma cell lines". International Journal of Molecular Medicine 44, no. 2 (2019): 437-446. https://doi.org/10.3892/ijmm.2019.4220