Src homology phosphotyrosyl phosphatase 2 mediates
 cisplatin-related drug resistance by inhibiting apoptosis 
and activating the Ras/PI3K/Akt1/survivin pathway in lung cancer cells

Tang,Chunlan; Luo,Hu; Luo,Dan; Yang,Heping; Zhou,Xiangdong

doi:10.3892/or.2017.6109

Src homology phosphotyrosyl phosphatase 2 mediates cisplatin-related drug resistance by inhibiting apoptosis and activating the Ras/PI3K/Akt1/survivin pathway in lung cancer cells

Authors:
- Chunlan Tang
- Hu Luo
- Dan Luo
- Heping Yang
- Xiangdong Zhou
View Affiliations

Affiliations: Department of Respiratory Medicine, The First Affiliated Hospital of The Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
Published online on: November 24, 2017 https://doi.org/10.3892/or.2017.6109
Pages: 611-618

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cisplatin resistance is a major cause of chemotherapeutic failure in lung cancer patients. Unraveling the molecular mechanisms underlying cisplatin (CDDP) resistance is important in lung cancer therapeutics. To explore the role of Src homology phosphotyrosyl phosphatase 2 (SHP2) in the development of cisplatin resistance in lung cancer and the underlying mechanism, we established stable SHP2‑overexpressing H446‑SHP2-OE cells and SHP2‑knockdown H446/CDDP‑SHP2-shRNA cells derived from H446 and H446/CDDP (cisplatin-resistant) parental lung cancer cells. The cell viability and apoptosis of these cells exposed to CDDP were observed to determine the influence of SHP2 on drug resistance. In addition, the expression of SHP2, Ras, Akt1 and survivin was assessed by western blot analysis after the lung cancer cells were challenged by cisplatin or silenced by Ras siRNA. As a result, the 50% inhibitory concentration (IC50) of the H446-SHP2-OE cells exposed to CDDP increased from 1.01 to 1.218 µg/ml vs. the H446-control vector cells. The percentage of apoptotic cells was smaller in the H446-SHP2-OE cells vs. the H446-control vector cells after cisplatin challenge. In addition, the expression of Ras, pAkt1, Akt1 and survivin in the H446/CDDP cells was significantly increased vs. the H446 cells. Furthermore, the IC50 of the H446/CDDP‑SHP2‑shRNA cells exposed to CDDP decreased from 11.92 to 4.382 µg/ml vs. the H446/CDDP‑mock cells. There were significantly more apoptotic cells among the H446/CDDP‑SHP2-shRNA cells vs. the H446/CDDP-mock cells exposed to cisplatin. A smaller percentage of the H446/CDDP-SHP2-shRNA cells vs. the H446/CDDP‑mock cells was observed. In addition, the expression of pAkt1 and survivin in the H446, H446/CDDP and H446/CDDP-mock cells was increased upon exposure to cisplatin however, a corresponding change was not observed in the H446/CDDP-SHP2-shRNA cells. Upon Ras RNA silencing with cisplatin, the Ras expression was significantly decreased in the H446, H446-SHP2-OE and H446/CDDP cells. However, upon Ras RNA interference, the SHP2 expression was not significantly changed, but the expression of Akt1, pAkt1 and survivin was significantly increased in the H446-SHP2-OE and H446/CDDP cells. In conclusion, SHP2 is a new cisplatin resistance-related phosphatase in lung cancer, which inhibits apoptosis by activating the Ras/PI3K/Akt1/survivin signaling pathway.

View Figures

View References

1	Torre LA, Siegel RL and Jemal A: Lung cancer statistics. Adv Exp Med Biol. 893:1–19. 2016. View Article : Google Scholar : PubMed/NCBI
2	Rivera MP: Lung cancer in women: Differences in epidemiology, biology, histology, and treatment outcomes. Semin Respir Crit Care Med. 34:792–801. 2013. View Article : Google Scholar : PubMed/NCBI
3	Mohan V, Agarwal R and Singh RP: A novel alkaloid, evodiamine causes nuclear localization of cytochrome-c and induces apoptosis independent of p53 in human lung cancer cells. Biochem Biophys Res Commun. 477:1065–1071. 2016. View Article : Google Scholar : PubMed/NCBI
4	D'Amico TA: Angiogenesis in non-small cell lung cancer. Semin Thorac Cardiovasc Surg. 16:13–18. 2004. View Article : Google Scholar : PubMed/NCBI
5	Müller-Tidow C, Diederichs S, Thomas M and Serve H: Genome-wide screening for prognosis-predicting genes in early-stage non-small-cell lung cancer. Lung Cancer. 45:S145–S150. 2004. View Article : Google Scholar : PubMed/NCBI
6	Rich JN and Bao S: Chemotherapy and cancer stem cells. Cell Stem Cell. 1:353–355. 2007. View Article : Google Scholar : PubMed/NCBI
7	Dittrich PS and Manz A: Lab-on-a-chip: Microfluidics in drug discovery. Nat Rev Drug Discov. 5:210–218. 2006. View Article : Google Scholar : PubMed/NCBI
8	Sampsonas F, Ryan D, McPhillips D and Breen DP: Molecular testing and personalized treatment of lung cancer. Curr Mol Pharmacol. 7:22–32. 2014. View Article : Google Scholar : PubMed/NCBI
9	Dimou A and Papadimitrakopoulou V: Non-small cell lung cancer beyond biomarkers: The evolving landscape of clinical trial design. J Pers Med. 4:386–401. 2014. View Article : Google Scholar : PubMed/NCBI
10	Pass HI, Lavilla C, Canino C, Goparaju C, Preiss J, Noreen S, Blandino G and Cioce M: Inhibition of the colony-stimulating-factor-1 receptor affects the resistance of lung cancer cells to cisplatin. Oncotarget. 7:56408–56421. 2016. View Article : Google Scholar : PubMed/NCBI
11	Gower A, Wang Y and Giaccone G: Oncogenic drivers, targeted therapies, and acquired resistance in non-small-cell lung cancer. J Mol Med (Berl). 92:697–707. 2014. View Article : Google Scholar : PubMed/NCBI
12	Kachalaki S, Ebrahimi M, Mohamed Khosroshahi L, Mohammadinejad S and Baradaran B: Cancer chemoresistance; biochemical and molecular aspects: a brief overview. Eur J Pharm Sci. 89:20–30. 2016. View Article : Google Scholar : PubMed/NCBI
13	Chen WX, Liu XM, Lv MM, Chen L, Zhao JH, Zhong SL, Ji MH, Hu Q, Luo Z, Wu JZ, et al: Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs. PLoS One. 9:e952402014. View Article : Google Scholar : PubMed/NCBI
14	Holohan C, Van Schaeybroeck S, Longley DB and Johnston PG: Cancer drug resistance: An evolving paradigm. Nat Rev Cancer. 13:714–726. 2013. View Article : Google Scholar : PubMed/NCBI
15	Ardizzoni A, Boni L, Tiseo M, Fossella FV, Schiller JH, Paesmans M, Radosavljevic D, Paccagnella A, Zatloukal P, Mazzanti P, et al CISCA (Cisplatin vs. Carboplatin) Meta-analysis Group, : Cisplatin- vs. carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: An individual patient data meta-analysis. J Natl Cancer Inst. 99:847–857. 2007. View Article : Google Scholar : PubMed/NCBI
16	Torigoe T, Izumi H, Ishiguchi H, Yoshida Y, Tanabe M, Yoshida T, Igarashi T, Niina I, Wakasugi T, Imaizumi T, et al: Cisplatin resistance and transcription factors. Curr Med Chem Anticancer Agents. 5:15–27. 2005. View Article : Google Scholar : PubMed/NCBI
17	Mo EP, Zhang RR, Xu J, Zhang H, Wang XX, Tan QT, Liu FL, Jiang RW and Cai SH: Calotropin from Asclepias curasavica induces cell cycle arrest and apoptosis in cisplatin-resistant lung cancer cells. Biochem Biophys Res Commun. 478:710–715. 2016. View Article : Google Scholar : PubMed/NCBI
18	Florea AM and Büsselberg D: Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and induced side effects. Cancers (Basel). 3:1351–1371. 2011. View Article : Google Scholar : PubMed/NCBI
19	Xie Y, Ma X, Gu L, Li H, Chen L, Li X, Gao Y, Fan Y, Zhang Y, Yao Y, et al: Prognostic and clinicopathological significance of survivin expression in renal cell carcinoma: A systematic review and meta-analysis. Sci Rep. 6:297942016. View Article : Google Scholar : PubMed/NCBI
20	Zeng LF, Zhang RY, Yu ZH, Li S, Wu L, Gunawan AM, Lane BS, Mali RS, Li X, Chan RJ, et al: Therapeutic potential of targeting the oncogenic SHP2 phosphatase. J Med Chem. 57:6594–6609. 2014. View Article : Google Scholar : PubMed/NCBI
21	Ren Y, Chen Z, Chen L, Fang B, Win-Piazza H, Haura E, Koomen JM and Wu J: Critical role of Shp2 in tumor growth involving regulation of c-Myc. Genes Cancer. 1:994–1007. 2010. View Article : Google Scholar : PubMed/NCBI
22	Chan G, Kalaitzidis D and Neel BG: The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metastasis Rev. 27:179–192. 2008. View Article : Google Scholar : PubMed/NCBI
23	Yang X, Dutta U and Shaw LM: SHP2 mediates the localized activation of Fyn downstream of the α6β4 integrin to promote carcinoma invasion. Mol Cell Biol. 30:5306–5317. 2010. View Article : Google Scholar : PubMed/NCBI
24	Cheng SQ, Fan HY, Xu X, Gao WW, Lv SG, Ye MH, Wu MJ, Shen XL, Cheng ZJ, Zhu XG and Zhang Y: Over-expression of LRIG1 suppresses biological function of pituitary adenoma via attenuation of PI3K/AKT and Ras/Raf/ERK pathways in vivo and in vitro. JJ Huazhong Univ Sci Technolog Med Sci. 36:558–563. 2016. View Article : Google Scholar
25	Malumbres M and Barbacid M: RAS oncogenes: The first 30 years. Nat Rev Cancer. 3:459–465. 2003. View Article : Google Scholar : PubMed/NCBI
26	Giltnane JM and Balko JM: Rationale for targeting the Ras/MAPK pathway in triple-negative breast cancer. Discov Med. 17:275–283. 2014.PubMed/NCBI
27	Ksionda O, Melton AA, Bache J, Tenhagen M, Bakker J, Harvey R, Winter SS, Rubio I and Roose JP: RasGRP1 overexpression in T-ALL increases basal nucleotide exchange on Ras rendering the Ras/PI3K/Akt pathway responsive to protumorigenic cytokines. Oncogene. 35:3658–3668. 2016. View Article : Google Scholar : PubMed/NCBI
28	Zhou XD and Agazie YM: Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells. Cell Death Differ. 15:988–996. 2008. View Article : Google Scholar : PubMed/NCBI
29	Tang C, Luo D, Yang H, Wang Q, Zhang R, Liu G and Zhou X: Expression of SHP2 and related markers in non-small cell lung cancer: a tissue microarray study of 80 cases. Appl Immunohistochem Mol Morphol. 21:386–394. 2013. View Article : Google Scholar : PubMed/NCBI
30	Li S, Shi H, Ji F, Wang B, Feng Q, Feng X, Jia Z, Zhao Q and Qian G: The human lung cancer drug resistance-related gene BC006151 regulates chemosensitivity in H446/CDDP cells. Biol Pharm Bull. 33:1285–1290. 2010. View Article : Google Scholar : PubMed/NCBI
31	Tang C, Zhou X, Yang H, Wang Q and Zhang R: Expression and its clinical significance of SHP2 in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi. 13:98–101. 2010.(in Chinese). PubMed/NCBI