Autophagy is described to be involved in homeostasis, development and disease, both as a survival and a death process. Its involvement in cell death proceeds from interrelationships with the apoptotic pathway. We focused on survival autophagy and investigated its interplays with the apoptotic machinery. We found that while Mcl-1 remained ineffective, Bcl-2 and Bcl-xL were required for starved cells to display a fully functional autophagic pathway as shown by proteolysis activity and detection of autophagic vesicles. Such pro-autophagic functions of Bcl-2 and Bcl-xL were independent of Bax. However they appeared to operate through non redundant mechanisms as Bcl-xL wielded a tighter control than Bcl-2 over the regulation of autophagy: unlike Bcl-2, Bcl-xL and Atg7 manipulation yielded identical phenotypes suggesting they could be components of the same signalling pathway; Bcl-xL subcellular localisation was modified upon starvation, and importantly Bcl-xL acted independently of Beclin 1. Still an intact BH3-binding site was required for Bcl-xL to stimulate a fully functional autophagic pathway. This study highlights that, in addition to their well-established anti-death function during apoptosis, Bcl-2 and Bcl-xL have a broader role in cell survival. Should Bcl-2 and Bcl-xL stand at the cross-roads between pro-survival and pro-death autophagy, this study introduces the new concept that the regulation of autophagy by Bcl-2 and Bcl-xL is adjusted according to its survival or death outcome.

Glioblastoma Multiforme (GBM) tumors are the most common type of brain tumors. These tumors are in general very malignant and can be characterized as rapidly progressive astrocytomas. The pathological characteristics of these tumors are exemplified by an active invasiveness, necrosis and a specialized form of angiogenesis, known as microvascular hyperplasia. These pathological features are thought to be due to tissue hypoxia. Cells that are under hypoxic stress can either develop an adaptive response that includes increasing the rate of glycolysis and angiogenesis or undergo cell death by promoting apoptosis and/or necrosis. The ability of tumor cells to maintain a balance between an adaptation to hypoxia and cell death is regulated by a family of transcription factors called hypoxia-inducing factors (HIF), which are essential for the regulation of the expression of a large number of hypoxia-responsive genes. The hypothesis that tumor hypoxia would facilitate the likelihood of metastases, tumor recurrence, resistance to chemotherapy and radiotherapy and the invasive potential; all of which culminate in a decrease in patient survival. In this review we will summarize the role of hypoxia in GBM with regard to drug therapy and toxicity and attempt to describe the possible interactions between hypoxia and apoptosis.

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