Relationship of the p75 neurotrophin receptor (p75NTR) and hypoxic response and treatment resistance in malignant gliomas.
e13026 Background: Malignant gliomas (MGs) are resistant to Radiotherapy (RT). The molecular pathways that produce resistance to therapy and ability to tolerate hypoxia are poorly understood. We previously found that the p75NTR causes invasion & proliferation of MGs/Brain Tumor Initiating Cells (BTICs). We think MGs use the neurotrophin-rich brain environment as a survival advantage to resist treatment by expressing the p75NTR. We hypothesize that hypoxia cause p75NTR proteolysis which produces HIF-1α stabilization and activation of hypoxic responses. This repertoire of hypoxic responses leads to resistance to both hypoxia & radiotherapy (RT) and account for MG recurrence. Methods: We used glioma cells and BTICs they express very low or and high levels of p75NTR and manipulated the expression of p75NTR by shRNAs and activation by mutant receptors and pharmacological inhibitors. We exposed these cells to hypoxia and radiation treatment and performed biochemical and functional assays. We have also used paired pre and post-RT frozen patient specimens. Gene expression profiles were analyzed for patients using microarray expression data for 516 primary GBM patients from the TCGA and 239 patients from Moffitt’s Total Cancer Care (TCC) project. Results: We found that inhibiting p75NTR pharmacologically significantly reduced invasion/proliferation of MGs/BTICs in vitro & in vivo. We have also found that p75NTR is required for HIF-1α stabilization and VEGF expression in MGs/BTICs in vitro & in vivo, that p75NTR expressing MGs/BTICs are very resistant to hypoxia & RT in vitro, and these effects are reversed with inhibition of p75NTR signaling. In addition, p75NTR expression and its cleavage are associated with treatment resistance in patient specimens. We also found using TCGA and Moffitt patient specimen data that the p75NTR/Siah2/PHD axis is expressed in MG patients and associated with RT resistance/poor prognosis. Conclusions: These results suggest that p75NTR expression/cleavage are required for HIF-1α pathway activation and hence the phenotype of MGs/BTICs and their treatment resistance. Targeting the p75NTR signaling axis therefore will provide novel therapeutic approaches.