The influence of SRPK1 on glioma apoptosis, metastasis, and angiogenesis through the PI3K/Akt signaling pathway under normoxia
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.
KeywordsSRPK1 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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