Downregulation of Src enhances the cytotoxic effect of temozolomide through AKT in glioma

Wang,Zengguang; Sun,Jikui; Li,Xue; Yang,Shuyuan; Yue,Shuyuan; Zhang,Jianning; Yang,Xuejun; Zhu,Tao; Jiang,Rongcai; Yang,Weidong

doi:10.3892/or.2013.2240

Downregulation of Src enhances the cytotoxic effect of temozolomide through AKT in glioma

Authors:
- Zengguang Wang
- Jikui Sun
- Xue Li
- Shuyuan Yang
- Shuyuan Yue
- Jianning Zhang
- Xuejun Yang
- Tao Zhu
- Rongcai Jiang
- Weidong Yang
View Affiliations

Affiliations: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
Published online on: January 17, 2013 https://doi.org/10.3892/or.2013.2240
Pages: 1395-1398

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Src is an attractive target since it is overexpressed in a number of malignancies, including glioma. However, the mechanism of Src signaling as well as its silencing effect on temozolomide in glioma is not well known. We hypothesized that downregulation of Src may enhance the cytotoxic effect of temozolomide on glioma. As expected, Src was overexpressed in glioblastoma multiforme (GBM) compared with normal brain tissues. Src silencing suppressed tumor proliferation and induced apoptosis in glioma. In addition, Src silencing combined with temozolomide treatment resulted in significant inhibition of tumor growth. These effects may be mediated by AKT which is a downstream effector of Src, since downregulation of AKT exhibited a similar effect as Src siRNA when combined with temozolomide. Finally, we demonstrated that overexpression of AKT suppressed the enhanced cytotoxic effect of temozolomide mediated by Src silencing. Thus, the present study demonstrated that Src plays a biologically significant role in tumor proliferation and apoptosis and enhances the cytotoxic effect of temozolomide through AKT supression in glioma.

View Figures

View References

1	Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
2	Gabayan AJ, Green SB, Sanan A, et al: GliaSite brachytherapy for treatment of recurrent malignant gliomas: a retrospective multi-institutional analysis. Neurosurgery. 58:701–709. 2006. View Article : Google Scholar : PubMed/NCBI
3	Lasky JL III, Choe M and Nakano I: Cancer stem cells in pediatric brain tumors. Curr Stem Cell Res Ther. 4:298–305. 2009. View Article : Google Scholar : PubMed/NCBI
4	Besch R, Poeck H, Hohenauer T, et al: Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells. J Clin Invest. 119:2399–2411. 2009.PubMed/NCBI
5	Parsons SJ and Parsons JT: Src family kinases, key regulators of signal transduction. Oncogene. 23:7906–7909. 2004. View Article : Google Scholar : PubMed/NCBI
6	Thomas SM and Brugge JS: Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 13:513–609. 1997. View Article : Google Scholar : PubMed/NCBI
7	Ahluwalia MS, de Groot J, Liu WM and Gladson CL: Targeting SRC in glioblastoma tumors and brain metastases: rationale and preclinical studies. Cancer Lett. 298:139–149. 2010. View Article : Google Scholar : PubMed/NCBI
8	Kassenbrock CK, Hunter S, Garl P, Johnson GL and Anderson SM: Inhibition of Src family kinases blocks epidermal growth factor (EGF)-induced activation of Akt, phosphorylation of c-Cbl, and ubiquitination of the EGF receptor. J Biol Chem. 277:24967–24975. 2002. View Article : Google Scholar : PubMed/NCBI
9	Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR and Parsons JT: Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol. 14:1680–1688. 1994.PubMed/NCBI
10	Testa JR and Bellacosa A: AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA. 98:10983–10985. 2001. View Article : Google Scholar : PubMed/NCBI
11	Vuori K, Hirai H, Aizawa S and Ruoslahti E: Introduction of p130cas signaling complex formation upon integrin-mediated cell adhesion: a role for Src family kinases. Mol Cell Biol. 16:2606–2613. 1996.PubMed/NCBI
12	Westhoff MA, Serrels B, Fincham VJ, Frame MC and Carragher NO: SRC-mediated phosphorylation of focal adhesion kinase couples actin and adhesion dynamics to survival signaling. Mol Cell Biol. 24:8113–8133. 2004. View Article : Google Scholar : PubMed/NCBI
13	Conway AM, Rakhit S, Pyne S and Pyne NJ: Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle: role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase. Biochem J. 337:171–177. 1999. View Article : Google Scholar
14	Su B and Karin M: Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol. 8:402–411. 1996. View Article : Google Scholar : PubMed/NCBI
15	Rous P: A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J Exp Med. 13:397–411. 1911. View Article : Google Scholar : PubMed/NCBI
16	Martin GS: Rous sarcoma virus: a function required for the maintenance of the transformed state. Nature. 227:1021–1023. 1970. View Article : Google Scholar : PubMed/NCBI
17	Stehelin D, Varmus HE, Bishop JM and Vogt PK: DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature. 260:170–173. 1976. View Article : Google Scholar : PubMed/NCBI
18	Stettner MR, Wang W, Nabors LB, et al: Lyn kinase activity is the predominant cellular SRC kinase activity in glioblastoma tumor cells. Cancer Res. 65:5535–5543. 2005. View Article : Google Scholar : PubMed/NCBI
19	West KA, Castillo SS and Dennis PA: Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat. 5:234–248. 2002. View Article : Google Scholar : PubMed/NCBI
20	Bellacosa A, Kumar CC, Di Cristofano A and Testa JR: Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 94:29–86. 2005. View Article : Google Scholar : PubMed/NCBI