Analysing the role of SERPINE1 network in the pathogenesis of human glioblastoma

Abstract

AbstractBackgroundGlioblastoma multiforme (GBM) is one of the most aggressive and difficult to treat brain tumour in humans with a 5 year survival rate of less than 6%. SERPINE1 is a novel tumour receptor found on GBM that modulates the progression of this cancer through growth signals and remodelling of the extracellular matrix. Hence, we investigated the role of SERPINE1 and its network proteins in pathogenesis of GBM and assessed its targetability.Material and methodsNetwork proteins of SERPINE1 in homo sapiens was identified using the String database, and the affinity of the protein-protein interaction of this network was analysed using Chimera software. The expression profile of SERPINE1 in the different brain regions was evaluated to correlate its relevance to GBM pathology. Selected small molecules fromCalotropis giganteawere screened using AutoDock vina to assess targetability of human SERPINE1.ResultsVTN, PLG, TGFB1, VWF, FGF2 and CXCR1 were identified as the major network proteins of SERPINE1. The strongest interaction was observed between SERPINE1 and FGF2 (42884 H-bonds) followed by CXCR1 (20279 H-bonds). Our results suggest that SERPINE1 and its network proteins identified here play a vital role in GBM development and progression through brain parenchyma by creating the prime microenvironment for carcinogenesis, tumour invasion and migration. The highest expression of SERPINE1 was observed in the pons, medulla, midbrain, corpus callosum and spinal cord. Expression of SERPINE1 was consistent with high grade lesions of GBM, suggesting association of SERPINE1 with advanced stages of GBM. The selected small molecules fromCalotropis giganteawere observed to have therapeutically feasible binding affinity (140 - 550 μM) and predicted efficacy (290 - 1115 μM) against human SERPINE1.ConclusionSERPINE1 plays a vital role in the progression of GBM through its critical network proteins identified in this study. The expression of SERPINE1 aligns with the advanced stages of GBM. Small molecules fromCalotropis giganteatested in this study can serve as lead compounds for developing novel anti-SERPINE1 therapeutics for advanced stages of GBM.