br DUBs in regulation of critical steps in tumor
DUBs in regulation of critical steps in tumor metastasis Tumor metastasis comprises a complicated series of biological processes in terms of the invasion-metastasis cascade that requires cancer PP121 synthesis to (1) migrate and invade from the origin sites through the extracellular matrix (ECM) to the stromal cell layers, (2) ingress into the blood vessels, otherwise known as intravasation, (3) survive during the transportation through the blood vessels, (4) egress out of the vessels termed extravasation into the distant organs, (5) survive and form micrometastasis, and (6) restart the proliferation to generate macrometastasis (Fig. 1 & Table 1) (Valastyan & Weinberg, 2011). In this review, we will discuss the emerging regulatory roles of DUBs in cellular signaling pathways critical for tumor metastasis such as EMT, self-renewal, apoptosis (anoikis) resistance, microenvironmental interactions, which are important processes contributing to the tumor metastasis (Fig. 2 & Table 1). Accordingly, small molecule inhibitors against DUBs have recently received a prominent focus in the field of anti-cancer therapies.
DUBs in regulation of apoptosis pathways in cancers The intrinsic connection between apoptosis is limited to the tumor initiation but tumor metastasis (Mehlen & Puisieux, 2006). Results from the previous works demonstrated several avenues for apoptosis in regulating cancer metastasis, including (1) blockade of metastatic dissemination by killing misplaced cells (Su et al., 2015); (2) death escape from the immune suppression enhances the survival of metastatic cells (Levy, Roberti, & Mordoh, 2011); (3) survival from the environment of ROS produced by endothelial cells when crossing the vessel or tissue barrier during the extravasation step (Eccles & Welch, 2007); and (4) survival from the hypoxic conditions and insufficiency of cytokines to achieve successful colonization at their destination sites (Azab, De La Puente, Vij, & Azab, 2013). Apoptosis is a cellular self-destruction program in response to multiple cellular stresses to maintain cellular homeostasis. Two routes of apoptosis, the extrinsic and intrinsic, both involve a complex network of signaling transduction leading to the activation of caspases, which could be simply divided to two subtypes: the ‘initiator’ caspases (caspase-2, -8, -9, or -10) and ‘executioner’ caspases (e.g., caspase-3 or -7). Activation of initiator caspases upon apoptotic stimuli followed by cleavage of executioner caspases are the key events of apoptosis (Fernald & Kurokawa, 2013). In extrinsic pathway, in response to the engagement of extracellular ligands by cell surface receptors, a death-inducing signal complex (DISC) is formed to activate the initiator caspases-8 and -10. The DISC is a complex structure containing different components (such as c-FLIP, FADD, and RIP) that together determine whether apoptosis becomes activated in response to different stimuli in different cell types. The efficiency of apoptosis signal transduction is dependent on the DISC formation since the activation of initiator caspases relies heavily on proximity for autoactivation (Yang, 2015). The expression of death signal sensors can be regulated independently from the protein synthesis and degradation in an ubiquitin-dependent manner. The conjugated ubiquitin can serve as an address and transport death signaling sensors to their designated cellular compartments (Menges, Altomare, & Testa, 2009). The intrinsic pathway, on the other hand, is initiated by the activation of BH3-only proteins which are usually transcriptionally activated by apoptosis stimuli. But there is one exception: BID is activated (termed tBID) by caspase cleavage (by caspases-2 or -8/10) (Czabotar, Lessene, Strasser, & Adams, 2014). The activated multi-BH domain proteins induced by activation of BH3-only proteins then form oligomers to induce the permeabilization of mitochondrial outer membrane (MOMP) which allows the characterized release of cytochrome c and second mitochondria-derived activator of caspases (SMAC) into cytoplasm (Green & Llambi, 2015). Cytochrome c then binds to the adaptor protein apoptotic protease-activating factor 1 (APAF-1) to form a multi-protein complex termed apoptosome, within which the caspase-9 initiates caspase-3 and caspase-7 leading to apoptosis. SMAC, as an inhibitory protein for inhibitor of apoptosis protein (IAPs), especially XIAP, enhances the activity of caspase cascade activated by cytochrome c (Hamacher-Brady and Brady, 2015, Hamacher-Brady et al., 2014).