Abstract
Glioblastoma multiforme (GBM) is the most aggressive CNS tumor and is characterized by a very high frequency of clinical relapse after therapy and thus by a dismal prognosis, which strongly compromises patients survival. We have recently identified the small molecule SI113, as a potent and selective inhibitor of SGK1, a serine/threonine protein kinase, that modulates several oncogenic signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation and perturbs cell cycle progression by modulating SGK1-related substrates. SI113 is also able to strongly and consistently block, in vitro and in vivo, growth and survival of human hepatocellular-carcinomas, either used as a single agent or in combination with ionizing radiations.In the present paper we aim to study the effect of SI113 on human GBM cell lines with variable p53 expression. Cell viability, cell death, caspase activation and cell cycle progression were then analyzed by FACS and WB-based assays, after exposure to SI113, with or without oxidative stress and ionizing radiations. Moreover, autophagy and related reticulum stress response were evaluated.We show here, that i) SGK1 is over-expressed in highly malignant gliomas and that the treatment with SI113 leads to ii) significant increase in caspase-mediated apoptotic cell death in GBM cell lines but not in normal fibroblasts; iii)enhancement of the effects of ionizing radiations; iv) modulation of the response to oxidative reticulum stress; v) induction of cytotoxic autophagy.Evidence reported here underlines the therapeutic potential of SI113 in GBM, suggesting a new therapeutic strategy either alone or in combination with radiotherapy.
Highlights
Malignant gliomas are the most frequent adult primary brain tumors and among these, glioblastoma multiforme (GBM) represent approximately 70% of glial tumors
That i) serum- and glucocorticoid-regulated kinase 1 (SGK1) is over-expressed in highly malignant gliomas and that the treatment with SI113 leads to ii) significant increase in caspase-mediated apoptotic cell death in Glioblastoma multiforme (GBM) cell lines but not in normal fibroblasts; iii)enhancement of the effects of ionizing radiations; iv) modulation of the response to oxidative reticulum stress; v) induction of cytotoxic autophagy
SGK1 specific inhibitors have been tested in several neoplastic models, including colon and hepatocellular carcinoma [22,23,24, 47,48,49]
Summary
Malignant gliomas are the most frequent adult primary brain tumors and among these, glioblastoma multiforme (GBM) represent approximately 70% of glial tumors. SGK1 is regulated at different levels by insulin [8,9,10], IGF-1 [11], glucocorticoids [12] and IL-2 [13] and, in turn, modulates survival and proliferative signals in normal and cancer cells. SGK1 modulates RANBP1 abundance at the transcriptional level via SP1 activation and phosphorylation on Serine 59, affecting taxol sensitivity in these cells [21]. Taken together, all these lines of evidence point to SGK1 as a key element in the development and/or progression of human cancer
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