Hypoxia Transcriptomic Modifications Induced by Proton Irradiation in U87 Glioblastoma Multiforme Cell Line.

Valentina Bravatà,Emanuele Scifoni,Walter Tinganelli,Giorgio Russo,Olga Sokol,Giada Petringa,Francesco P Cammarata,Marco Calvaruso,Giusi I Forte,Giuseppe A.P Cirrone,Luigi Minafra

doi:10.3390/jpm11040308

Abstract

In Glioblastoma Multiforme (GBM), hypoxia is associated with radioresistance and poor prognosis. Since standard GBM treatments are not always effective, new strategies are needed to overcome resistance to therapeutic treatments, including radiotherapy (RT). Our study aims to shed light on the biomarker network involved in a hypoxic (0.2% oxygen) GBM cell line that is radioresistant after proton therapy (PT). For cultivating cells in acute hypoxia, GSI’s hypoxic chambers were used. Cells were irradiated in the middle of a spread-out Bragg peak with increasing PT doses to verify the greater radioresistance in hypoxic conditions. Whole-genome cDNA microarray gene expression analyses were performed for samples treated with 2 and 10 Gy to highlight biological processes activated in GBM following PT in the hypoxic condition. We describe cell survival response and significant deregulated pathways responsible for the cell death/survival balance and gene signatures linked to the PT/hypoxia configurations assayed. Highlighting the molecular pathways involved in GBM resistance following hypoxia and ionizing radiation (IR), this work could suggest new molecular targets, allowing the development of targeted drugs to be suggested in association with PT.

Highlights

Glioblastoma Multiforme (GBM) is the most malignant and the most common tumor among glial neoplasms
This condition is a feature found in several tumors, and it represents an indication of a poor prognosis
The plot demonstrates a substantial increase in cell survival in hypoxic conditions with an OERS=10% = 1.69 ± 0.36

Summary

Introduction

Glioblastoma Multiforme (GBM) is the most malignant and the most common tumor among glial neoplasms It is characterized by an anaplastic, poorly differentiated, and highly cellular grade IV astrocytoma with a peak of incidence between 45 and 70 years [1]. Hypoxia is a pathophysiological condition that generally arises due to the rapid proliferation of cancer cells as they outgrow their blood supply, depleting cells of nutrients and available oxygen [1,4]. This condition is a feature found in several tumors, and it represents an indication of a poor prognosis. Tumor hypoxia substantially diminishes the efficacy of conventional anticancer approaches

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