The ADAMs Metalloprotease Family as Targets of Anticancer Therapy - Report Example

The ADAMs metalloprotease family are useful targets of anticancer therapy Proteases and kinases have fundamental functions in most biological and pathological procedures including cancer. The effects mediated by these enzymes are essentially different. Under physiological conditions phosphorylation can be reversed but proteolysis remains irretrievable. The irrevocable nature of protease catalyzed reactions and the common notion that proteases were non-specific damaging molecules lead to an overlooking them as important biological regulators. Consequently, it has been reported that proteases play active highly selective slicing of particular substrates. Upon this insight, many parallels have been drawn between these two groups of enzymes. Sequence from both organisms models and human depict that massive multiplicity in the proteases and kinases functions derive their functionality from fruition. Furthermore, the human degradome and kinome reveal catalytic domains. These distinct domains are associated to have impacts on substrate specificity, kinetic properties and kinetic properties (López-Otín & Hunter, 2010). Phosphorylation by protein kinases can switch protease activity on or off. Among proteases activated by kinases are the metalloproteinases such as those of a disintegrin and metalloproteinase (ADAM) family. Proteases can also switch kinases on or off. For instance, caspases and calpains can get rid of inhibitory domains from kinases leading to their activation. Of importance in this review is the ability of proteases to modulate kinase functions in more sophisticated mechanisms. An example is the conversion of a receptor tyrosine kinase (RTK) ectodomain to a soluble protein or production of intracellular fragments with novel signaling mechanism. These processes are well depicted by the shedding and regulated intramembrane proteolysis (RIPping) events in which ADAMs modify the signaling properties. The cross-talk between proteases and kinases is relevant in pathological and physiological conditions especially for stimulating cell proliferation, invasion and survival in cancer (López-Otín & Hunter, 2010). The expansion of tumors require invasion of neighboring stroma, which is often linked to destruction of parenchyma and remodeling of the extracellular matrix. This process is significantly aided by the catalytic activity of extracellular proteases which facilitate movement. Additionally, these catalytic proteases mediate the release of matrix-bound growth factors and expose cryptic matrix sites for adhesion. Consequently, it is insightful to predict that extracellular proteases play a vital role in the process of expansion of tumors and their metastatic growth. Moreover, they also partake in the control of tumor angiogenesis and in the process of immunological surveillance. As a result, the overall contribution of these proteases to the process of tumorigenesis is broad and continuous (Thomas-Tikhonenko, 2010).  Significant in this review are a group of extracellular enzymes called adamalysins. A majority of these enzymes have been identified and successfully cloned over the past years. Therefore, they have rapidly gained recognition as important contributors in the progression and metastasis of cancer. Adamalysins include a group of extracellular enzymes with structural motifs of disintegrin and metalloprotease domains. There are two major subgroups in the adamalysins family namely, membrane-anchored ADAMs (A Disintegrin And Metalloprotease) and the secreted ADAMTSs (A Disintegrin And Metalloprotease with Thrombospondin repeats). The existence of a zinc-dependent metalloprotease domain places these enzymes within the super family of metzincins. This important category also comprises matrixins (MMPs) serralisins and astacins. Adamalysins show structural features within the disintegrin domains that are similar to the reprolysin family of snake venomases. Conversely, this domain does not appear to show functional analogy to proteases of snake venom. Thus, the disintegrin domain does not compete with endogenous matrix proteins for interaction to integrins. However, under spatial circumstance, the ADAMs and ADAMTSs have been reported to enhance binding and spreading of cells in an integrins dependent fashion. Adamalysins also interrelate with a number of extracellular proteins without catalysis. This in effect enhances their participation in formation rather than damage of the extracellular matrix. Nonetheless, it is imperative to note that adamalysins are usually under tight regulatory control mechanisms. Consequently, their presence in extracellular matrix does not necessarily translate to proteolytic activity (Nigel & Lendeckel 2005).  A disintegrin and metalloproteinase (ADAM) comprise a family of transmembrane and secreted proteins having approximately 750 amino acids in length. These proteins function in cell adhesion and proteolytic processing of the ectodomains of diverse signaling molecules and cell surface receptors. Ectodomain shedding of a number of substrates is coupled to their subsequent cleavage by regulated intramembrane proteolysis. In the process, there is generation of nucleus targeted stimuli among them being Notch in the forefront. In cancer, a range of ADAMs enhances the malignant nature of tumors by inducing cell proliferation via EGFR receptor activation. Furthermore, the malignancy aspect is stimulated by induction of epithelial-mesenchymal transition through E-cadherin cleavage. As a result, particular ADAMs have become attractive targets for drug development especially anticancer drugs. It is essential that researchers understand the complex repertoire of physiological roles of these important molecules (Edwards, Handsley & Pennington, 2008). The ADAM family of proteinases comprise of 38 diverse membrane anchored proteins with numerous undertakings in cell-matrix and cell-cell associations. This is notwithstanding their role in processing and degradation of substrates. The constituents of this important protein family have exceptional structural morphology exemplified by a prodomain, cysteine-rich, metalloprotease and disintegrin. Furthermore, the members of this family possess epidermal growth factor-like transmembrane and a cytoplasmic domain (López-Otín & Hunter, 2010). ADAMs play crucial roles in diverse biological processes ranging from fertilization to adipogenesis. This can be attributed to their multi-domain structure in addition to their wide range of expression patterns. However, under pathological settings, ADAMs are well known for their roles as inducible shedasses. Basically, in this respect, they act as enzymes which catalyze the cleavage of surface proteins. Specifically, the ADAM17 also referred to as TACE (Tumor Necrosis Factor-alpha Converting Enzymes) advances cleavage an activation of many growth factors and receptors. ADAM17 plays a crucial role in the ectodomain shedding of many soluble proteins including HB-EGF, amphiregulin and TNF-α. Since Tumor Necrosis Factor-α is a potent proinflammatory cytokine, inhibitors of ADAM17 may be helpful in tackling ulcerative colitis, respiratory disease and other diseases. ADAM9 cleaves and releases EGF, fibroblast growth factor receptor 2 and HB-EGF. ADAM10 is involved in the ectodomain shedding of a number of substrates such as adhesion molecules of cadherins and CD44. ADAM12 is known to take part in the ectodomain shedding of various potential substrates such as Epidermal Growth Factors (EGFs). Furthermore, ADAM12 regulates the transforming growth factor-β (TGF-β) receptor trafficking (Edwards, Handsley & Pennington, 2008). The ectodomain shedding of proHB-EGF results in the production of two fragments namely, extracellular fragment (HB-EGF) and a remnant fragment (HB-EGF-C). In recent studies, the promyelocytic leukemia zinc finger (PLZF) was identified as a binding protein of the cytoplasmic tail of the proHB-EGF.PLZF is a transcription repressor of cyclin A and therefore down regulates cell growth. It is able to achieve this activity by inhibiting the entry or progression into the S-phase of the cell cycle. Therefore, ADAMs are capable of regulating adhesion and motility of cells as well as mediating the shedding of growth factors. Epidermal growth factors (EGF) family as well as their receptors, the human epidermal growth factor receptors (HERs), are expressed in a number of tissues such as mesenchymal, epithelial and cancers. The epidermal growth factors and HER receptors are involved in cancer cell activities. Cancer cell behaviors affected by the EGF and HER receptors include invasion, excessive growth and blood vessel formation. A key stage in the triggering of EGRF ligands and HER family is the ectodomain shedding of the ligands. Once the EGFR ligands are shed into soluble conformations, they are capable of binding to HER receptors. Members of a disintegrin and a metalloproteinase family have been implicated in the ligand shedding of EGFR. The human epidermal growth factor receptors (HERs) alternatively referred to as the ErbB family of tyrosine kinase receptors and their ligands are important regulators of cancer cell growth. Additionally, these receptors and their EGFR ligands play critical role in controlling metastasis and angiogenesis. EGF ligands are cleaved from their transmembrane form in a process called ectodomain shedding and the soluble form of the EGF ligand is released via paracrine or autocrine mechanisms. ADAM family members take part in ectodomain shedding of EGF ligands as well as other membrane proteins such cytokines, growth factors, cytokine receptors and growth factor receptor (Hiromi, 2009). Fig. 1 Mechanism of EGFR transactivation through pro-EGFR ligands shedding by ADAMs. G-protein-coupled receptors (GPCRs) with second messengers, such as elevation of intracellular Ca2+, activation of protein kinase C (PKC) and generation of reactive oxygen species (ROS) by UV-irradiation induces ADAM activation (López-Otín & Hunter, 2010). The fundamental nature of the biological processes regulated by ADAM proteinases dictates that dysregulation of these enzymes will contribute in human disease pathogenesis. Consequently, ADAMs family proteinases play significant role in their involvement in signaling pathways that are dysregulated in cancers and tumor progression. In a majority of cancer cases, ADAMs are up regulated. This has provided tangible hypotheses of potential targeting of ADAMs family members as a new approach in antitumor therapy. As active metalloproteinases, ADAMs may play a role in enhancement of tumor invasion and metastasis via cleavage of extracellular matrix proteins. For instance, ADAM9 is capable of cleaving laminin and promoting invasion. ADAMs may also modulate directly tumor cell adhesion through binding to integrins and proteoglycans. Isolated domains of ADAMs may have potential effects on tumorigenesis as depicted by the anti-angiogenic and anti-metastatic actions of disintegrin domain of ADAM15 (Hiromi, 2009). G-protein coupled receptors (GPCRs) have been shown to activate a number of ADAMs proteinases and to transactivate epidermal growth factor receptor (EGFR). ADAM activation by GPCRs requires second messengers such as increased intracellular calcium ions. Moreover, the triggering process may be aided by reactive oxygen species and protein kinase C (PKC) as second messengers. Ultraviolet radiation of the skin cancer cells triggers ADAMs and stimulates EGFR ligand shedding and transactivation of EGFR. It is postulated that the ultraviolet radiation induces the production of reactive oxygen species (ROS). It is then these reactive oxygen species that stimulate ADAM9 and ADAM17 which subsequently cleave EFGR ligands. The soluble form of the EFGR ligands, known as ampuregulin (AR) later interacts and binds to EGFR hence induce the proliferation of skin cancer. This is notably the activity that occurs in squamous cell carcinoma. Basal cell carcinoma is the most common form of skin tumor. This type of skin cancer hardly metastasizes but is locally invasive and highly damaging. ADAM10, ADAM12 and ADAM17 are elevated at the peripheral margin in comparison to the central areas of BCC tumor nest cells. ADAM10 and ADAM12 expression levels are increased within the deep margin of invading tumor nest cells. On the other hand, ADAM17 expression is elevated in the superficial areas. Therefore, these subtypes of the ADAM proteinases family exhibit different expression profiles in basal cell carcinoma. This indicates that within the BCC histologic subtypes, the various ADAMs play different roles in the pathogenesis of basal cell carcinoma. Therefore, inhibition of the EGFR pathways in cancer cells has been reported to block the progression of cell cycle, apoptosis and metastasis. Various EGFR blockers have been evaluated, and some of these are now used in clinical interventions. Examples of EGFR blockers include tyrosine kinase inhibitors, anti-EGFR monoclonal antibodies, immunoconjugates, ligand conjugates and antisense oligonucleotides (Hiromi, 2009). In summary, targeting ADAMs in the coming up with cancer therapies has focused on the modulation of the HER signaling mechanism. The efficiency of ADAN10 and ADAM17 inhibitors has been well documented in cancer cells and animal models. This particular inhibitor also acts in tandem with the chemotherapeutic agent, paclitaxel in reducing tumor volume in mouse models. ADAMs have several target molecules and hence there is a greater risk of multiple and severe side effects by their inhibitors. One ADAM inhibitor affects EGFR ligand shedding in addition to adhesion molecules and cytokines. Conclusively, if ADAM inhibitors are used in clinical aspects, they ought to be limited in terms of specific disease conditions and for a shorter time period. Moreover, specific inhibitors against single ADAM members are required because in many cases, ADAM inhibitors affect various ADAM members. The advance of new drugs that inhibit nuclear translocation of CTF of EGFR ligands is very promising for cancer therapy. This is because, in combination with HER inhibitors, these drugs will entirely shut down the growth signals of the HER and EFGR families with minimal side effects (Okazaki & Nabeshima, 2012). References Hiromi, K. (2009). EGFR ligands and their signaling scissors, ADAMs, as new molecular targets for anticancer treatments. Journal of Dermatological Science, 148-153. Edwards, D., Handsley, M., Pennington, C. (2008). The ADAM metalloproteinases. Mol Aspects Med, 258-289. Nigel, H., Uwe, L. (2005). The ADAM Family of Proteases. UK: Springer, p6-15. Andrei, T. (2010). Cancer Genome and Tumor Microenvironment. USA: Springer. p295-307 Okazaki, I., Nabeshima, K. (2012). Introduction: MMPs, ADAMs/ADAMTSs research products to achieve big dream. Anti-Cancer Agents in Medicinal Chemistry, 688-706. López-Otín, C., Hunter, T. (2010). The regulatory crosstalk between kinases and proteases in cancer. Cancer Research, 4676-4686. Foidart, J-M., Muschel. (2002). Proteases and Their Inhibitors in Cancer Metastasis. USA: Springer. p130-140. Supuran, C., Winum, J. (2009). Drug Design of Zinc-Enzyme Inhibitors: Functional, Structural, and Disease Applications. New Jersey Canada: John Wiley & Sons. p9-20. Bonavida, B. (Springer, 2008). Sensitization of Cancer Cells for Chemo/Immuno/Radio-Therapy. 2nd ed. Los Angeles, CA.USA: Humana Press. p144-149. Atta-ur-Rahman, M., Choudhary, I. (2010). Frontiers in Anti-Cancer Drug Discovery, Volume (1. 3rd ed. USA: Bentham Science. p186-188. Innocenti, F. (2008). Genomics and Pharmacogenomics in Anticancer Drug Development and Clinical Response. Chicago USA: Humana press. p120-123. Srivastava, R. (2012). Stem Cells and Human Diseases. Kansa City USA: Springer. p296-602. Mendelson, K. (January, 2011). The Role of ADAM (a Disintegrin and Metalloproteinase) Proteins in Pericytes and PDGFRbeta Signaling. Cornell University: Cornell University. p30-42. Berry, E., Bosonea, A., Wang, X., Fernandez-Patron, C., (2012). Insights into the activity, differential expression, mutual regulation, and functions of matrix metalloproteinases and A disintegrin and metalloproteinases in hypertension and cardiac disease. Journal of Vascular Research, 52-68. Choi, J.E., Kim, D.S., Kim, E.J., Chae, M.H., Cha, S.I., Kim, C.H., Jheon, S., Park, J.Y. (2008). Aberrant methylation of ADAMTS1 in non-small cell lung cancer. Cancer Genetics and Cytogenetics, 80-84. Moncada-Pazos, A., Obaya, A.J., Fraga, M.F., Viloria, C.G., Capellá, G., Gausachs, M., Esteller, M., Cal, S. (2009). The ADAMTS12 metalloprotease gene is epigenetically silenced in tumor cells and transcriptionally activated in the stroma during progression of colon cancer. Journal of Cell Science, 2906-2913. Read More