Tumor Biology

, Volume 37, Issue 5, pp 6331–6336 | Cite as

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

  • Wei Liu
  • Jinfeng Ning
  • Chunhong Li
  • Jing Hu
  • Qingwei Meng
  • Hailing Lu
  • Li CaiEmail author
Original Article


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.


Lung cancer NSCLC SphK2 Gefitinib EGFR-TKI PC-9/GR cells Proliferation Apoptosis Chemoresistance 



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).

Compliance with ethical standards

Conflicts of interest



  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 4.
    Mok TS et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. 6.
    Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008;9:139–50.CrossRefPubMedGoogle Scholar
  7. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.PubMedGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 14.
    Pyne N, Pyne S. Sphingosine 1-phosphate and cancer. Nat Rev Cancer. 2010;10:489–503.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gao P, Smith CD. Ablation of sphingosine kinase-2 inhibits tumor ell proliferation and migration. Mol Cancer Res. 2011;9:1509–19.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Wei Liu
    • 1
  • Jinfeng Ning
    • 2
  • Chunhong Li
    • 1
  • Jing Hu
    • 1
  • Qingwei Meng
    • 1
  • Hailing Lu
    • 1
  • Li Cai
    • 1
    Email author
  1. 1.The Fourth Department of Medical OncologyHarbin Medical University Cancer HospitalHarbinChina
  2. 2.The Thoracic Surgery DepartmentHarbin Medical University Cancer HospitalHarbinChina

Personalised recommendations