Tmic-21. kinomic profiling of glioblastoma cells reveals plcg1 as a common pro-survival signaling node under restricted glucose

Understanding the effects of tumor microenvironments on glioblastoma (GBM; grade IV astrocytoma) is required to develop anti-tumor treatments that will be effective in vivo. Physiologic levels of glucose are not modeled in traditional cell culture conditions and can be restricted in tumor niches. Our prior data demonstrated that nutrient restriction promotes phenotypes associated with a highly tumorigenic and therapy resistant subset of GBM cells called brain tumor initiating cells (BTICs). We therefore sought to profile the differences in kinase activity in GBM cells cultured in restricted glucose to identify pathways that could be targeted with small molecule inhibitors. Using the PamStation12 platform, we examined the ability of protein lysates from standard and low glucose cultured GBM cells to phosphorylate 144 tyrosine and 144 serine and threonine phosphorylatable peptides that correspond to phosphorylation sites in known proteins. When results from a classical and proneural xenograft were compared, we determined common changes to peptides corresponding to Phospholipase C, Gamma 1 (PLCG1) and Raf1 peptides. Using PLC and Raf inhibitors, we found a significantly stronger growth inhibitory effect of the PLC inhibitor U73122 under restricted glucose conditions. In contrast, Raf inhibitors were significantly growth inhibitory regardless of the nutrient level tested. Together, our data demonstrate that kinase activity is altered in low glucose conditions in GBM and that kino...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: TUMOR MICROENVIRONMENT Source Type: research