In response to stress signals caused by decreased intracellular metabolite concentrations, autophagy prevents cell death by replenishing

metabolites [12]; however, autophagy can also cause cell death, depending on the stimuli and environment [13]. This review will focus on gastrointestinal www.selleckchem.com/products/AZD6244.html cancers. We will initially describe the dysregulation of Bcl-2 family in gastrointestinal cancers. In the major part of this review, we will discuss how autophagy is regulated by Bcl-2 family proteins and BH3 mimetics. We will also concentrate upon the function of autophagy as a cell-fate decision machinery and explore molecular mechanisms that link autophagy to cellular outcome in response to BH3 mimetics treatment. Cancers of the gastrointestinal tract account for more than a third of total cancer incidence and nearly half of the cancer-related deaths FRAX597 solubility dmso in the world [14]. Bcl-2 family dysregulation has been demonstrated in gastrointestinal cancers (Table 1). The altered expression of Bcl-2 family members has been reported in transcriptional, translational and post-translational levels. Mutations of Bcl-2 family members have also been documented. Notably, some of these abnormalities have been shown to correlate with clinicopathological parameters and disease outcomes

including overall survival in cancer patients [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36] and [37]. These findings not only underscore a pivotal role of Bcl-2 family in tumorigenesis, Galeterone but also highlight the possibility of targeting the Bcl-2 family members as a potential therapeutic avenue for the treatment of gastrointestinal cancers. The mitochondrion serves not only as the cell’s powerhouse, but also as a center for integration of signals for apoptosis vs. survival. Capable of releasing a plethora of pro-apoptotic proteins into the cytoplasm, mitochondrion is a necessary site of extensive regulation in apoptosis. The Bcl-2 family is an important group

of proteins that was first noted to regulate the release of apoptotic proteins from the mitochondria, specifically by causing mitochondrial outer membrane permeabilization (MOMP). A consequence of MOMP is the release of intermembrane space proteins such as cytochrome c into the cytoplasm, where they allosterically activate the adaptor protein Apaf-1 to initiate the cascade of caspases that cleave substrates leading to cellular apoptosis. Even without caspase activation, the reduced respiration following cytochrome c release soon triggers a backup cell death [38]. In this way, the Bcl-2 proteins family consists of upstream activators of apoptotic signaling in relation to MOMP [39]. On the basis of various structural and functional characteristics, the Bcl-2 family proteins can be divided into three functional subgroups (Fig. 1).