Tumor Biology

, Volume 37, Issue 7, pp 8699–8707 | Cite as

Expression of SRPK1 in gliomas and its role in glioma cell lines viability

  • Ioanna Sigala
  • Konstantinos I. Tsamis
  • Anna Gousia
  • George Alexiou
  • Spyridon Voulgaris
  • Thomas Giannakouros
  • Athanassios P. Kyritsis
  • Eleni Nikolakaki
Original Article


Among factors regulating the splicing of major importance is serine/arginine protein kinase 1 (SRPK1) that phosphorylates SR splicing factors. SRPK1 is expressed in the mammalian central nervous system in a region- and neuron-specific manner. Based on previous observations that glial cells are practically devoid of SRPK1 and reports showing aberrant expression of SRPK1 in numerous tumors, but with conflicting roles, this study aims to investigate the expression of SRPK1 in glioma and its influence on tumor cell biological features. As shown by immunohistochemical analysis, malignant glioma cells express SRPK1 in glioblastomas with significant association between SRPK1 expression and patients’ survival. SRPK1 expression was also significantly upregulated at the messenger RNA (mRNA) and protein level in glioma cell lines. Small interfering RNA-mediated downregulation of SRPK1 had little effect on cell viability, while it slightly enhanced the sensitivity of cells to killing by cisplatin. These results support the idea that at least in vitro, the effect of SRPK1 knockdown on the viability of glioma cell lines is rather limited, while the in vivo effects could be attributed to the modulation of angiogenesis by SRPK1.


SRPK1 Gliomas Cell viabilty Chemotherapeutic agents Cisplatin 5-FU 



This work was co-financed by the European Union and the Greek State, Ministry of Education and Religious Affairs/General Secretariat for Research and Technology, as well as by Josef and Esther Gani Foundation (Ioannina, Greece).

Compliance with ethical standards

The study was approved by the Review Board of the Neurosurgical Institute of Ioannina.

Conflicts of interest



  1. 1.
    Louis DN. Molecular pathology of malignant gliomas. Annu Rev Pathol Mech Dis. 2006;1:97–117.CrossRefGoogle Scholar
  2. 2.
    Liu Y, Shete S, Etzel CJ, Scheurer M, Alexiou G, Armstrong G, et al. Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 genes involved in the double-strand break repair pathway predict glioblastoma survival. J Clin Oncol. 2010;28:2467–74.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A. Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129:829–48.CrossRefPubMedGoogle Scholar
  4. 4.
    Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12:587–98.CrossRefPubMedGoogle Scholar
  5. 5.
    Kaida D, Schneider-Poetsch T, Yoshida M. Splicing in oncogenesis and tumor suppression. Cancer Sci. 2012;103:1611–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Giannakouros T, Nikolakaki E, Mylonis I, Georgatsou E. Serine-arginine protein kinases: a small protein kinase family with a large cellular presence. FEBS J. 2011;278:570–86.CrossRefPubMedGoogle Scholar
  7. 7.
    Zahler AM, Neugebauer KM, Lane WS, Roth MB. Distinct functions of SR proteins in alternative pre-mRNA splicing. Science. 1993;260:219–22.CrossRefPubMedGoogle Scholar
  8. 8.
    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
  9. 9.
    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
  10. 10.
    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
  11. 11.
    Hishizawa M, Imada K, Sakai T, Ueda M, Hori T, Uchiyama T. Serological identification of adult T-cell leukaemia-associated antigens. Br J Haematol. 2005;130:382–90.CrossRefPubMedGoogle Scholar
  12. 12.
    Sanidas I, Kotoula V, Ritou E, Daans J, Lenz C, Mairhofer M, et al. The ratio of SRPK1/SRPK1a regulates erythroid differentiation in K562 leukaemic cells. Biochim Biophys Acta. 2010;1803:1319–31.CrossRefPubMedGoogle Scholar
  13. 13.
    Odunsi K, Mhawech-Fauceglia P, Andrews C, Beck A, Amuwo O, Lele S, et al. Elevated expression of the serine-arginine protein kinase 1 gene in ovarian cancer and its role in Cisplatin cytotoxicity in vitro. PLoS One. 2012;7(12):e51030.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Gout S, Brambilla E, Boudria A, Drissi R, Lantuejoul S, Gazzeri S, et al. Abnormal expression of the pre-mRNA splicing regulators SRSF1, SRSF2, SRPK1 and SRPK2 in non small cell lung carcinoma. PLoS One. 2012;7(10):e46539.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    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
  16. 16.
    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 Educ. 2013;4:727–35.CrossRefGoogle Scholar
  17. 17.
    Gammons MV, Lucas R, Dean R, Coupland SE, Oltean S, Bates DO. Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma. Br J Cancer. 2014;111:477–85.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Mavrou A, Brakspear K, Hamdollah-Zadeh M, Damodaran G, Babaei-Jadidi R, Oxley J, et al. Serine-arginine protein kinase 1 (SRPK1) inhibition as a potential novel targeted therapeutic strategy in prostate cancer. Oncogene. 2014. doi: 10.1038/onc.2014.360.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Schenk PW, Stoop H, Bokemeyer C, Mayer F, Stoter G, Oosterhuis JW, et al. Resistance to platinum-containing chemotherapy in testicular germ cell tumors is associated with downregulation of the protein kinase SRPK1. Neoplasia. 2004;6:297–301.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Plasencia C, Martínez-Balibrea E, Martinez-Cardús A, Quinn DI, Abad A, Neamati N. Expression analysis of genes involved in oxaliplatin response and development of oxaliplatin-resistant HT29 colon cancer cells. Int J Oncol. 2006;29:225–35.PubMedGoogle Scholar
  21. 21.
    Mytilinaios DG, Tsamis KI, Nikolakaki E, Giannakouros T. Distribution of SRPK1 in human brain. J Chem Neuroanat. 2012;43:20–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Chang Y, Wu Q, Tian T, Li L, Guo X, Feng Z, et al. The influence of SRPK1 on glioma apoptosis, metastasis, and angiogenesis through the PI3K/Akt signaling pathway under normoxia. Tumour Biol. 2015.Google Scholar
  23. 23.
    Nowak DG, Amin EM, Rennel ES, Hoareau-Aveilla C, Gammons M, Damodoran G, et al. Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to anti-angiogenic isoforms: a novel therapeutic strategy for angiogenesis. J Biol Chem. 2010;285:5532–40.CrossRefPubMedGoogle Scholar
  24. 24.
    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
  25. 25.
    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
  26. 26.
    Wang F, Zhou J, Xie X, Hu J, Chen L, Hu Q, et al. Involvement of SRPK1 in cisplatin resistance related to long non-coding RNA UCA1 in human ovarian cancer cells. Neoplasma. 2015;62:432–8.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Ioanna Sigala
    • 1
  • Konstantinos I. Tsamis
    • 2
  • Anna Gousia
    • 3
  • George Alexiou
    • 2
    • 4
  • Spyridon Voulgaris
    • 4
  • Thomas Giannakouros
    • 1
  • Athanassios P. Kyritsis
    • 2
  • Eleni Nikolakaki
    • 1
  1. 1.Laboratory of Biochemistry, Department of ChemistryAristotelian UniversityThessalonikiGreece
  2. 2.Neurosurgical Institute, Medical SchoolUniversity of IoanninaIoanninaGreece
  3. 3.Department of Pathology, Medical SchoolUniversity of IoanninaIoanninaGreece
  4. 4.Department of Neurosurgery, Medical SchoolUniversity of IoanninaIoanninaGreece

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