PDGFR inhibition mediated intracellular signalling in C6 glioma growth and migration: role of ERK and ROCK pathway
Aberrant PDGFR (Platelet derived growth factor receptor) signalling in brain tumors and gliomas is one of the primary cause of tumor progression. PDGFR stimulation by its ligand and the role of its downstream mediators such as extracellular regulated kinases (ERK1/2), PI3K and ROCK pathways have not been thoroughly investigated. The present study sought to investigate the role of PDGF receptor signalling inhibition on suppression of rat C6 glioma growth and migration. Treatment of C6 cells with PDGFR inhibitor, AG1295 caused a significant reduction in migration and proliferation by regulating the ERK and ROCK signalling. Subsequently, PDGFR blocking was demonstrated to regulate cytoskeleton reorganization by modulating the Actin-pMLC reorganization and pERK–FAK–Paxillin complex formation which may further regulate the C6 glioma migration. Further, other malignant behaviour of C6 glioma such as anchorage independent growth, adhesion, invasion and sphere forming abilities were found to be impaired by PDGFR blocking. PDGFR inhibition further regulates the C6 glioma tumor behaviour by inducing gene expression of GFAP, BDNF, and MECP2 and down regulating FAK expression. In conclusion, our data elucidate novel mechanisms involve in PDGFR inhibition mediated inhibition of C6 glioma growth and migration which can be a future potential target for the treatment of glioma.
KeywordsC6 glioma Migration PDGFR ERK ROCK
This work was funded by a grant from University Grant Commission (F. No.41-148/2012 (SR) dated 13th July 2012), New Delhi, India. Currently, Ms. Juhi Singh is being supported by fellowship grant awarded by CSIR-SRF, New Delhi (CSIR-SRF Project No: 09/114(0206)/2016-EMR-I dated 31-3-17). We also thankful to DBT-MSUB-ILSPARE programme for the confocal microscopy and qPCR facility at Dr. Vikram Sarabhai Science Block, Faculty of Science, The M.S University of Baroda, Vadodara.
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Conflict of interest
The Authors report no conflict of interest.
- Bogatcheva NV, Zemskova MA, Poirier C, Mirzapoiazova T, Kolosova I, Bresnick AR, Verin AD (2011) The suppression of myosin light chain (MLC) phosphorylation during the response to lipopolysaccharide (LPS): beneficial or detrimental to endothelial barrier? J Cell Physiol 226:3132–3146CrossRefGoogle Scholar
- Lind CRP, Gray CW, Pearson AG, Cameron RE, O’Carroll SJ, Narayan PJ, Dragunow M (2006) The mitogen-activated/extracellular signal-regulated kinase kinase 1/2 inhibitor U0126 induces glial fibrillary acidic protein expression and reduces the proliferation and migration of C6 glioma cells. Neuroscience 141:1925–1933CrossRefGoogle Scholar
- Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese NA (2002) Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res 62:3729–3735Google Scholar
- Popescu AM, Alexandru O, Brindusa C, Purcaru SO, Tache DE, Tataranu LG, Dricu A (2015) Targeting the VEGF and PDGF signaling pathway in glioblastoma treatment. Int J Clin Exp Pathol 8:7825Google Scholar
- Strawn LM, Mann E, Elliger SS, Chu LM, Germain LL, Niederfellner G, Shawver LK (1994) Inhibition of glioma cell growth by a truncated platelet-derived growth factor-beta receptor. J Biol Chem 269:21215–21222Google Scholar
- Xu M, Bian S, Li J, He J, Chen H, Ge L, Mo Y (2016) MeCP2 suppresses LIN28A expression via binding to its methylated-CpG islands in pancreatic cancer cells. Oncotarget 7:14476–14485Google Scholar
- Zohrabian VM, Forzani B, Chau Z, Murali RAJ, Jhanwar-Uniyal M (2009) Rho/ROCK and MAPK signaling pathways are involved in glioblastoma cell migration and proliferation. Anticancer Res 29:119–123Google Scholar