Tumor Biology

, Volume 36, Issue 8, pp 6083–6093 | Cite as

The influence of SRPK1 on glioma apoptosis, metastasis, and angiogenesis through the PI3K/Akt signaling pathway under normoxia

  • Yingwei Chang
  • Qianqian Wu
  • Ting Tian
  • Li Li
  • Xuyan Guo
  • Zhuoying Feng
  • Junchen Zhou
  • Luping Zhang
  • Shuai Zhou
  • Guoying Feng
  • Fengchan Han
  • Jun Yang
  • Fei Huang
Research Article


Gliomas, the most common primary brain tumors, have low survival rates and poorly defined molecular mechanisms to target for treatment. Serine/arginine SR protein kinases 1 (SRPK1) can highly and specifically phosphorylate the SR protein found in many tumors, which can influence cell proliferation and angiogenesis. However, the roles and regulatory mechanisms of SRPK1 in gliomas are not understood. The aim of this study was to determine the functions and regulation of SRPK1 in gliomas. We found that SRPK1 inhibition induces early apoptosis and significantly inhibits xenograft tumor growth. Our results indicate that SRPK1 affects Akt and eIF4E phosphorylation, Bax and Bcl-2 activation, and HIF-1 and VEGF production in glioma cells. Moreover, transfection of SRPK1 siRNA strongly reduced cell invasion and migration by regulating the expression of MMP2 and MMP9 and significantly decreased the volume of tumors and angiogenesis. We show here that a strong link exists among SRPK1, Akt, eIF4E, HIF-1, and VEGF activity that is functionally involved in apoptosis, metastasis, and angiogenesis of gliomas under normoxic conditions. Thus, SRPK1 may be a potential anticancer target to inhibit glioma progression.


SRPK1 Glioma Akt Metastasis Apoptosis Angiogenesis 



This study was supported by the Key Project of National Natural Science Foundation of Shandong Province (ZR 2009CL004) and China Postdoctoral Science Foundation (20100481466). We also acknowledge the Pharmaceutical Health Science and Technology Development Program of Shandong Province (2011QZ001) and National Natural Science Foundation of China (81171142/H0910, 81271092) for funding this research, as well as a Project of Shandong Province Higher Educational Science and Technology Program (J11LF61).

Conflicts of interest



  1. 1.
    Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 2012;485:502–6.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482:226–31.CrossRefPubMedGoogle Scholar
  3. 3.
    Gui JF, Lane WS, Fu XD. A serine kinase regulates intracellular localization of splicing factors in the cell cycle. Nature. 1994;369:678–82.CrossRefPubMedGoogle Scholar
  4. 4.
    Zhong XY, Ding JH, Adams JA, Ghosh G, Fu XD. Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones. Genes Dev. 2009;23:482–95.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Krishnakumar S, Mohan A, Kandalam M, Ramkumar HL, Venkatesan N, Das RR. SRPK1: a cisplatin sensitive protein expressed in retinoblastoma. Pediatr Blood Cancer. 2008;50:402–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Schenk PW, Boersma AW, Brandsma JA, den Dulk H, Burger H, Stoter G, et al. SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line. Cancer Res. 2001;61:6982–6.PubMedGoogle Scholar
  7. 7.
    Li XH, Song JW, Liu JL, Wu S, Wang LS, Gong LY, et al. Serine-arginine protein kinase 1 is associated with breast cancer progression and poor patient survival. Med Oncol. 2014;31:83.CrossRefPubMedGoogle Scholar
  8. 8.
    Hayes GM, Carrigan PE, Miller LJ. Serine-arginine protein kinase 1 overexpression is associated with tumorigenic imbalance in mitogen-activated protein kinase pathways in breast, colonic, and pancreatic carcinomas. Cancer Res. 2007;67:2072–80.CrossRefPubMedGoogle Scholar
  9. 9.
    Wang P, Zhou Z, Hu A, Ponte de Albuquerque C, Zhou Y, Hong L, et al. Both decreased and increased SRPK1 levels promote cancer by interfering with PHLPP-mediated dephosphorylation of Akt. Mol Cell. 2014;54:378–91.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Shultz JC, Goehe RW, Wijesinghe DS, Murudkar C, Hawkins AJ, Shay JW, et al. Alternative splicing of caspase 9 is modulated by the phosphoinositide 3-kinase/Akt pathway via phosphorylation of SRp30a. Cancer Res. 2010;70:9185–96.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Amin EM, Oltean S, Hua J, Gammons MV, Hamdollah-Zadeh M, Welsh GI, et al. WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. Cancer Cell. 2011;20:768–80.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 2000;60:1541–5.PubMedGoogle Scholar
  13. 13.
    Jiang BH, Jiang G, Zheng JZ, Lu Z, Hunter T, Vogt PK. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ. 2001;12:363–9.PubMedGoogle Scholar
  14. 14.
    Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 2000;14:391–6.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Pore N, Gupta AK, Cerniglia GJ, Maity A. HIV protease inhibitors decrease VEGF/HIF-1alpha expression and angiogenesis in glioblastoma cells. Neoplasia. 2006;8:889–95.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G. Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res. 2000;60:4693–6.PubMedGoogle Scholar
  17. 17.
    Giaccia A, Siim BG, Johnson RS. HIF-1 as a target for drug development. Nat Rev Drug Discov. 2003;2:803–11.CrossRefPubMedGoogle Scholar
  18. 18.
    Mavrakis KJ, Wendel HG. Translational control and cancer therapy. Cell Cycle. 2008;7:2791–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Harada H, Itasaka S, Kizaka-Kondoh S, Shibuya K, Morinibu A, Shinomiya K, et al. The Akt/mTOR pathway assures the synthesis of HIF-1alpha protein in a glucose- and reoxygenation-dependent manner in irradiated tumors. J Biol Chem. 2009;284:5332–42.CrossRefPubMedGoogle Scholar
  20. 20.
    Wu Q, Chang Y, Zhang L, Zhang Y, Tian T, Feng G, et al. SRPK1 dissimilarly impacts on the growth, metastasis, chemosensitivity and angiogenesis of glioma in normoxic and hypoxic conditions. J Cancer. 2013;4:727–35.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlowski JM, et al. A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res. 1987;47:3239–45.PubMedGoogle Scholar
  22. 22.
    Hirota K, Semenza GL. Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol. 2006;59:15–26.CrossRefPubMedGoogle Scholar
  23. 23.
    Liu LZ, Li C, Chen Q, Jing Y, Carpenter R, Jiang Y, et al. MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1alpha expression. PLoS ONE. 2011;6:e19139.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hayes GM, Carrigan PE, Beck AM, Miller LJ. Targeting the RNA splicing machinery as a novel treatment strategy for pancreatic carcinoma. Cancer Res. 2006;66:3819–27.CrossRefPubMedGoogle Scholar
  25. 25.
    Toker A, Chin YR. Akt-ing up on SRPK1: oncogene or tumor suppressor? Mol Cell. 2014;54:329–30.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Zhou B, Li Y, Deng Q, Wang H, Wang Y, Cai B, et al. SRPK1 contributes to malignancy of hepatocellular carcinoma through a possible mechanism involving PI3K/Akt. Mol Cell Biochem. 2013;379:191–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Tsuruta F, Masuyama N, Gotoh Y. The phosphatidylinositol 3-kinase (PI3K)-Akt pathway suppresses Bax translocation to mitochondria. J Biol Chem. 2002;277:14040–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhou Z, Qiu J, Liu W, Zhou Y, Plocinik RM, Li H, et al. The Akt-SRPK-SR axis constitutes a major pathway in transducing EGF signaling to regulate alternative splicing in the nucleus. Mol Cell. 2012;47:422–33.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Gotoh T, Terada K, Oyadomari S, Mori M. hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria. Cell Death Differ. 2004;11:390–402.CrossRefPubMedGoogle Scholar
  30. 30.
    Akbar AN, Borthwick NJ, Wickremasinghe RG, Panayoitidis P, Pilling D, Bofill M, et al. Interleukin-2 receptor common gamma-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax, bcl-xS) gene expression. Eur J Immunol. 1996;26:294–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74:609–19.CrossRefPubMedGoogle Scholar
  32. 32.
    Wang HY, Lin W, Dyck JA, Yeakley JM, Songyang Z, Cantley LC, et al. SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells. J Cell Biol. 1998;140:737–50.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Raithatha SA, Muzik H, Rewcastle NB, Johnston RN, Edwards DR, Forsyth PA. Localization of gelatinase-A and gelatinase-B mRNA and protein in human gliomas. Neuro-Oncol. 2000;2:145–50.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Colin C, Voutsinos-Porche B, Nanni I, Fina F, Metellus P, Intagliata D, et al. High expression of cathepsin B and plasminogen activator inhibitor type-1 are strong predictors of survival in glioblastomas. Acta Neuropathol. 2009;118:745–54.CrossRefPubMedGoogle Scholar
  35. 35.
    Bourboulia D, Jensen-Taubman S, Rittler MR, Han HY, Chatterjee T, Wei B, et al. Endogenous angiogenesis inhibitor blocks tumor growth via direct and indirect effects on tumor microenvironment. Am J Pathol. 2011;179:2589–600.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Yue X, Lan F, Yang W, Yang Y, Han L, Zhang A, et al. Interruption of beta-catenin suppresses the EGFR pathway by blocking multiple oncogenic targets in human glioma cells. Brain Res. 2010;1366:27–37.CrossRefPubMedGoogle Scholar
  37. 37.
    Kim JH, Park DK, Lee CH, Yoon DY. A new isoflavone glycitein 7-O-beta-D-glucoside 4″-O-methylate, isolated from Cordyceps militaris grown on germinated soybeans extract, inhibits EGF-induced mucus hypersecretion in the human lung mucoepidermoid cells. Phytother Res. 2012;26:1807–12.CrossRefPubMedGoogle Scholar
  38. 38.
    Blair KJ, Kiang A, Wang-Rodriguez J, Yu MA, Doherty JK, Ongkeko WM. EGF and bFGF promote invasion that is modulated by PI3/Akt kinase and Erk in vestibular schwannoma. Otol Neurotology. 2011;32:308–14.CrossRefGoogle Scholar
  39. 39.
    Oda T, Hirota K, Nishi K, Takabuchi S, Oda S, Yamada H, et al. Activation of hypoxia-inducible factor 1 during macrophage differentiation. Am J Physiol Cell Physiol. 2006;291:C104–13.CrossRefPubMedGoogle Scholar
  40. 40.
    Chen J, Weiss WA. Alternative splicing in cancer: implications for biology and therapy. Oncogene. 2015;34:1–14.CrossRefPubMedGoogle Scholar
  41. 41.
    Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001;21:3995–4004.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Chen PN, Hsieh YS, Chiou HL, Chu SC. Silibinin inhibits cell invasion through inactivation of both PI3K-Akt and MAPK signaling pathways. Chem Biol Interact. 2005;156:141–50.CrossRefPubMedGoogle Scholar
  43. 43.
    Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM, Semenza GL. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem. 2002;277:38205–11.CrossRefPubMedGoogle Scholar
  44. 44.
    Anczukow O, Rosenberg AZ, Akerman M, Das S, Zhan L, Karni R, et al. The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat Struct Mol Biol. 2012;19:220–8.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Lachance PE, Miron M, Raught B, Sonenberg N, Lasko P. Phosphorylation of eukaryotic translation initiation factor 4E is critical for growth. Mol Cell Biol. 2002;22:1656–63.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Kuniyasu H, Ellis LM, Evans DB, Abbruzzese JL, Fenoglio CJ, Bucana CD, et al. Relative expression of E-cadherin and type IV collagenase genes predicts disease outcome in patients with resectable pancreatic carcinoma. Clin Cancer Res. 1999;5:25–33.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yingwei Chang
    • 1
  • Qianqian Wu
    • 1
  • Ting Tian
    • 1
  • Li Li
    • 1
  • Xuyan Guo
    • 1
  • Zhuoying Feng
    • 1
  • Junchen Zhou
    • 1
  • Luping Zhang
    • 1
  • Shuai Zhou
    • 1
  • Guoying Feng
    • 1
  • Fengchan Han
    • 1
  • Jun Yang
    • 2
  • Fei Huang
    • 1
  1. 1.Institute of Human Anatomy and Histology and Embryology, Otology & Neuroscience CenterBinzhou Medical UniversityLaishan DistrictChina
  2. 2.NeurosurgeryBinzhou Medical University Yantai Affiliated HospitalMuping AreaChina

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