Apoptotic cell death modulation by ER stress and autophagy

Cancer is a highly complex disease which is caused by an upset of balance between cell growth and death. During cell transformation, abnormality in the machinery of apoptosis often occurs, resulting in a chemotherapy-resistant phenotype of cancerous cells. Endoplasmic reticulum stress (ER stress) and autophagic process are now representing serious candidates as alternative pathways to induce cell death in chemotherapy-resistant tumor cells. If on the one hand they induce cytoprotective functions to reestablish normal cellular homeostasis, on the other hand they contribute to an efficient cell killing when the stress is prolonged and unresolved. Therefore, harnessing stress-induced survival response, such as ER stress and autophagy, may represent a new anticancer strategy to induce cell death in apoptosis-resistant tumors. In line with this hypothesis, it has been recently shown that some chemotherapeutic agents overcome apoptosis-resistance through induction of both autophagy and ER stress. Thus, understanding the link between ER stress/apoptosis and autophagy/apoptosis induction may offer the opportunity to find out new targets to design more effective therapeutic regimes to treat cancer malignancies. Here, we show that: i) the down-regulation of the transcription factor E2F1, a key regulator of proliferation and cell death, represents a critical event in ER stress-induced apoptosis, unveiling E2F1 inactivation as a novel therapeutic strategy to increase the response of tumor cells to ER stress based anticancer treatments; ii) oncogenic activating mutation in B-RAF confers resistance to autophagy in response to both classical inducers (serum starvation and rapamycin), and to ER stress-induced apoptosis (fenretinide and velcade), suggesting that autophagy is required for efficient melanoma cell killing; iii) Ambra1, an essential regulator of autophagy, plays a role in the regulation of apoptosis, and consequently in the interplay between autophagy and apoptosis, underlining the functional link existing between these processes.