Abstract
Glioblastoma multiforme (GBM) continues to be the most frequently diagnosed and lethal primary brain tumor. Adjuvant chemo-radiotherapy remains the standard of care following surgical resection. In this study, using reverse phase protein arrays (RPPAs), we assessed the biological effects of radiation on signaling pathways to identify potential radiosensitizing molecular targets. We identified subsets of proteins with clearly concordant/discordant behavior between irradiated and non-irradiated GBM cells in vitro and in vivo. Moreover, we observed high expression of Forkhead box protein M1 (FOXM1) in irradiated GBM cells both in vitro and in vivo. Recent evidence of FOXM1 as a master regulator of metastasis and its important role in maintaining neural, progenitor, and GBM stem cells, intrigued us to validate it as a radiosensitizing target. Here we show that FOXM1 inhibition radiosensitizes GBM cells by abrogating genes associated with cell cycle progression and DNA repair, suggesting its role in cellular response to radiation. Further, we demonstrate that radiation induced stimulation of FOXM1 expression is dependent on STAT3 activation. Co-immunoprecipitation and co-localization assays revealed physical interaction of FOXM1 with phosphorylated STAT3 under radiation treatment. In conclusion, we hypothesize that FOXM1 regulates radioresistance via STAT3 in GBM cells. We also, show GBM patients with high FOXM1 expression have poor prognosis. Collectively our observations might open novel opportunities for targeting FOXM1 for effective GBM therapy.
Highlights
Glioblastoma multiforme or glioblastoma (GBM) continues to be the most frequently diagnosed and lethal of primary brain tumors
In the present study using reverse phase protein arrays (RPPAs) we assessed the biological effects of radiation on signaling pathways and demonstrate induction of Forkhead box protein M1 (FOXM1) with radiation treatment (RT)
We identified subsets of proteins with differential expression between GBM cells grown in vitro and those grown in vivo in an orthotopic mouse model (Figure 1A)
Summary
Glioblastoma multiforme or glioblastoma (GBM) continues to be the most frequently diagnosed and lethal of primary brain tumors. FOXM1 is a transcription factor and known to play an essential role in the regulation of a wide spectrum of biological processes, including cell proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, angiogenesis and apoptosis [4,5,6,7]. Recent evidence of FOXM1 as a master regulator of metastasis, over expression in human GBM and its important role in maintaining neural, progenitor, and GBM stem cells intrigued us to validate it as a radio sensitizing target [4,8,9]. We show that the www.impactjournals.com/oncotarget radiation induced FOXM1 expression is dependent on STAT3 activation. Both FOXM1 and STAT3 proteins interact and co-localize in the nucleus under RT. We hypothesize that; these proteins (FOXM1/STAT3) together regulate radio resistance in GBM cells
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