PDGFR inhibition mediated intracellular signalling in C6 glioma growth and migration: role of ERK and ROCK pathway

Abstract

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.

Alcam-a and Pdgfr-α are essential for the development of sclerotome derived stromal cells that support hematopoiesis in vivo

“…Therefore we hypothesized a possible cross-talk between Alcama and Pdgfr- α . It is known that PDGF signaling leads to an increase in AKT and ERK phosphorylation 34,35 . We firstly investigated the impact of alcama knock-down on pERK signaling in the caudal region at 26 hpf.…”

“…Since the involvement of PI3K in SCP migration was revealed, we then mutated two tyrosine residues in the intracellular domain of Pdgfr-α that are responsible for the binding of class IA (α/ α/ δ) PI3K to Pdgfr- α following its activation and autophosphorylation 34 (Fig. 4A), and we cloned the mutated or WT pdgfra ORF followed by a tandem HA-tag downstream of a hsp70 promoter 38 (hsp70:pdgfra-ΔPI3K-HA or hsp70:pdgfra WT -HA, respectively).…”

The Cytoskeleton—A Complex Interacting Meshwork

“…Inhibition of the RhoA target ROCK led to increased migration in glioma cells via an activation of Rac1 [507] and Rac1 inhibition was associated with reduced migration and invasion [507,508,509]. Contrasting these observations, other studies found ROCK inhibition associates with the reduced migration of glioma cells [510,511]. A possible explanation for this discrepancy might be due to biphasic effects of ROCK activity.…”

Neurons chemoattract cancer cells via MCP-1-CCR4-induced paxillin phosphorylation and activation in the cancer cell cytoskeleton

“…In hepatocellular carcinoma, Sorafenib combined with vitamin K1 significantly inhibited the hepatocellular carcinoma cell migration through decreased ERK1/2 phosphorylation (D'Alessandro et al 2018). Furthermore, inhibition of the platelet-derived growth factor receptor resulted in an obvious suppression of migration and proliferation in glioma cells via regulation of the FAK/paxillinERK signaling pathway (Singh et al 2018).…”