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Overexpression of Sphk2 is associated with gefitinib resistance in non-small cell lung cancer

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Tumor Biology

Abstract

Lung cancer is the major cause of cancer-related death worldwide, and 80 % of them are non-small cell lung cancer (NSCLC) cases. Recent studies have shown that sphingosine kinase 2 (SphK2) could promote tumor progression; however, whether SphK2 could affect the chemoresistance of NSCLC to chemotherapy remains unclear. To determine whether SphK2 serves as a potential therapeutic target of NSCLC, we utilized small interference RNA (siRNA) to knock down SphK2 expression in human NSCLC cells and analyzed their phenotypic changes. The data demonstrated that knockdown of SphK2 led to decreased proliferation and enhanced chemosensitivity and apoptosis to gefitinib in NSCLC cells. In this study, we describe the findings that overexpression of SphK2 promotes chemoresistance in NSCLC cells. Inhibition of SphK2 might be considered as a strategy in NSCLC treatment with gefitinib.

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References

  1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.

    Article  PubMed  Google Scholar 

  2. Crino L, Weder W, van Meerbeeck J, Felip E, Working Group ESMO. Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v103–15.

    Article  PubMed  Google Scholar 

  3. Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE collaborative group. J Clin Oncol. 2008;26:3552–9.

    Article  PubMed  Google Scholar 

  4. Mok TS et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57.

    Article  CAS  PubMed  Google Scholar 

  5. Brugger W et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29:4113–20.

    Article  CAS  PubMed  Google Scholar 

  6. Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008;9:139–50.

    Article  CAS  PubMed  Google Scholar 

  7. Shida D, Takabe K, Kapitonov D, Milstien S, Spiegel S. Targeting SphK1 as a new strategy against cancer. Curr Drug Targets. 2008;9:662–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Oskeritzian CA, Alvarez SE, Hait NC, Price MM, Milstien S, Spiegel S. Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions. Blood. 2008;111:4193–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Liu H, Chakravarty D, Maceyka M, Milstien S, Spiegel S. Sphingosine kinases: a novel family of lipid kinases. Prog Nucleic Acid Res Mol Biol. 2002;71:493–511.

    Article  CAS  PubMed  Google Scholar 

  10. Kris MG et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290:2149–58.

    Article  CAS  PubMed  Google Scholar 

  11. David O, Jett J, LeBeau H, Dy G, Hughes J, Friedman M, et al. Phospho-Akt overexpression in non-small cell lung cancer confers significant stage independent survival disadvantage. Clin Cancer Res. 2004;10:6865–71.

    Article  CAS  PubMed  Google Scholar 

  12. Brognard J, Clark AS, Ni Y, Dennis PA. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res. 2001;61:3986–97.

    CAS  PubMed  Google Scholar 

  13. Igarashi N, Okada T, Hayashi S, Fujita T, Jahangeer S, Nakamura S. Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis. J Biol Chem. 2003;47:46832–9.

    Article  Google Scholar 

  14. Pyne N, Pyne S. Sphingosine 1-phosphate and cancer. Nat Rev Cancer. 2010;10:489–503.

    Article  CAS  PubMed  Google Scholar 

  15. Sun DF, Gao ZH, Liu HP, Yuan Y, Qu XJ. Sphingosine-1-phosphate antagonizes the effect of all-trans-retinoic acid (ATRA) in a human colon cancer cell line by modulation of RARb expression. Cancer Lett. 2012;319:182–9.

    Article  CAS  PubMed  Google Scholar 

  16. French KJ, Schrecengost RS, Lee BD, Zhuang Y, Smith SN, Eberly JL, et al. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res. 2003;63:5962–9.

    CAS  PubMed  Google Scholar 

  17. Miller AV, Alvarez SE, Spiegel S, Lebman DA. Sphingosine kinases and sphingosine-1-phosphate are critical for transforming growth factor beta-induced extracellular signal-regulated kinase 1 and 2 activation and promotion of migration and invasion of esophageal cancer cells. Mol Cell Biol. 2008;28:4142–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gao P, Smith CD. Ablation of sphingosine kinase-2 inhibits tumor ell proliferation and migration. Mol Cancer Res. 2011;9:1509–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work is supported by National Natural Science Foundation of China grant (No. 81172214, 81572276 to LC), National Natural Science Youth Foundation of China grant (No. 81501960 to JH), Health Department of Heilongjiang Province of China grant (No. 2013086 to JN), Harbin Medical University Cancer Hospital of China grant (No. JJMS2014-04 to JN, JJZ2011-02 to CL), and Harbin Bureau of Science and Technology grant (No. 2015RAQYJ101 to JN).

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    Authors and Affiliations

    1. The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Haping Road 150, Harbin, 150040, China

      Wei Liu, Chunhong Li, Jing Hu, Qingwei Meng, Hailing Lu & Li Cai

    2. The Thoracic Surgery Department, Harbin Medical University Cancer Hospital, Harbin, 150040, China

      Jinfeng Ning

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    1. Wei Liu
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    2. Jinfeng Ning
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    3. Chunhong Li
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    4. Jing Hu
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    5. Qingwei Meng
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    6. Hailing Lu
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    7. Li Cai
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    Correspondence to Li Cai.

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    Wei Liu and Jinfeng Ning contributed equally to this work.

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    Liu, W., Ning, J., Li, C. et al. Overexpression of Sphk2 is associated with gefitinib resistance in non-small cell lung cancer. Tumor Biol. 37, 6331–6336 (2016). https://doi.org/10.1007/s13277-015-4480-1

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