br Enzyme activations Activated proteinases
Enzyme activations Activated proteinases can unleash a deluge of tissue damage (Zucker et al., 2009). Once activated, the essential enzymes such as serine proteases and cysteine proteases cannot discriminate between self and non-self, burning away self-tissues (Chien et al., 2009, Laskar et al., 2012, Choudhury et al., 2013, Phillips-Mason et al., 2014). Extracellular matrix (ECM) is a viscous cocktail of proteins, proteoglycans, and glycoproteins, providing tensile strength and viscoelasticity to tissues (Lu et al., 2011). ECM proteins such as elastin, fibronectin, laminin, and type IV collagen are manipulated (Lu et al., 2011, Yue, 2014). ECM proteins are degraded by the digestive action of matrix metalloproteinases (MMPs), the zinc-dependent endopeptidases/proteolytic enzymes (Vartak and Gemeinhart, 2007). Though new discoveries are constantly changing the classifications, the substrate-activity-based clustering of enzymes appears informative (Vartak and Gemeinhart, 2007). MMPs, owing to their proteolytic activities mediate a gamut of pathologies including arthritis, atherosclerosis, ulcers, periodontal disease, brain, liver cirrhosis, fibrotic lung disease, multiple sclerosis, endometriosis, pulmonary emphysema etc. (Amălinei et al., 2010). ProMMP-9 is activated in the stomach, which can cause gastric ulcer and gastric cancer (Carneiro et al., 2009, Choudhury et al., 2013). ProMMP-2 and proMMP-8 activation in saliva causes caries. MMP-7 is expressed by tumor Wnt-C59 receptor of epithelial and mesenchymal origin (Amălinei et al., 2010). Table 1 presents the pertinent data regarding the types and function of MMPs. For further information on the functional profile of MMPs, previously published works can be referred to (Klein and Bischoff, 2011). Tissue inhibitors of metalloproteinases (TIMPs), a type of extracellular proteins, regulate the MMPs. Inflammatory milieu increase TIMP-1 expression. TIMPs and MMPs are mutual inhibitory (Moore and Crocker, 2012). Cyclooxygenase-2 (COX-2) produces prostaglandin (PGE2), the pain mediator. COX-2 elaboration increases in the presence of cytokines, growth factors, microbial lipopolysaccharides (LPS), and insect chitins (Ricciotti and FitzGerald, 2011). Aromatase is a cytochromes P450 monooxygenase that converts androgens (C19) to estrogens (C18) (Demura et al., 2007, Izawa et al., 2008). Hyper-activity of this enzyme can generate excess local estrogen, leading to perturbation of glucose, and lipid, affecting brain function, ovulation, fertility etc. COX-2 and aromatase activity are directly related (Fowler et al., 2005, Sirianni et al., 2009, Basu et al., 2015). It is important to understand that all enzymes collaborate and co-ordinate to run the human systems and their functions. Perturbation of one can shake the others as well. The inflammatory enzymes COX-2 and aromatase require phospholipase C, and protein kinase C, among other array of enzymes for their functions. Glycosidases embrace a broad array of enzymes and they can activate in sub-optimal pH. Heparanase can express, degrading the proteoglycan heparan sulfate in the basement membrane and ECM, contributing to tumor invasion and metastasis (Koliopanos et al., 2001, Takaoka et al., 2003, Zheng et al., 2010). Focal adhesion kinase (FAK) is a tyrosine kinase, with role in cell adhesion, growth, proliferation (via the Ras/ERK/MAPK pathway), angiogenesis and migration etc. Tumorous tissues have higher expression of FAK, which regulate protein scaffoldings (Stevenson et al., 2012). Src family kinases (SFKs), a group of non-receptor tyrosine kinases, also play critical role in cell adhesion, invasion, proliferation, and angiogenesis. SFKs comprise nine family members (Src, Fyn, Yes, Blk, Yrk, Fgr, Hck, Lck and Lyn) that share similar structure and function. Overexpression of SFKs occurs frequently in tumor tissues (Kim et al., 2009, Guarino, 2010). SFKs interact with FAK for tumor cells invasion (Guarino, 2010). Kinases manipulate structural proteins like integrins, actins, GTPase-activating proteins, scaffold proteins (p130CAS and paxillin). Angiogenic growth factors as EGFR and the VEGF serve as tyrosine kinase receptors. The mammalian target of rapamycin (mTOR), a serine/threonine kinase, is activated by diverse stimuli, including growth factors, and signaling pathways as PI3K, mitogen-activated protein kinases (MAPK) and 5′ AMP-activated protein kinase (AMPK) (Pópulo et al., 2012).The Ras-MAPK pathway is common to a number of cancers (Dangle et al., 2009). The phosphoinositide 3-kinase (PI3K), when activated can communicate signal constitutively and exert oncogenicity (Vogt et al., 2010). Anomalous action of PI3K transduction pathway can interact with AKT and mTOR to cause a wide range of cancers (Liu et al., 2009, Fruman and Rommel, 2014). Fig. 1 illustrates the mechanism of enzyme cascade involved in tumorigenesis.