Therapeutics Targeting Matrix Metalloproteinases

Cathcart, Jillian; Pulkoski‐Gross, Ashleigh; Zucker, Stanley; Cao, Jian

doi:10.1002/9781118772287.ch5

Cited by 4 publications

(3 citation statements)

References 90 publications

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“…The different structures characterizing the various MMPs allow the accomplishment of multiple functions influencing several processes like cell behavior, apoptosis and cell proliferation. Oncological studies have shown that MMPs play several functions favoring tumor progression through the degradation of surrounding tissues, the modulation of growth factors and membrane receptors, as well as inflammatory proteins, adhesion molecules and chemo-attractive proteins [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Functional Roles of Matrix Metalloproteinases and Their Inhibitors in Melanoma

Napoli

Scuderi

Gattuso

et al. 2020

Cells

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The extracellular matrix (ECM) plays an important role in the regulation of the tissue microenvironment and in the maintenance of cellular homeostasis. Several proteins with a proteolytic activity toward several ECM components are involved in the regulation and remodeling of the ECM. Among these, Matrix Metalloproteinases (MMPs) are a class of peptidase able to remodel the ECM by favoring the tumor invasive processes. Of these peptidases, MMP-9 is the most involved in the development of cancer, including that of melanoma. Dysregulations of the MAPKs and PI3K/Akt signaling pathways can lead to an aberrant overexpression of MMP-9. Even ncRNAs are implicated in the aberrant production of MMP-9 protein, as well as other proteins responsible for the activation or inhibition of MMP-9, such as Osteopontin and Tissue Inhibitors of Metalloproteinases. Currently, there are different therapeutic approaches for melanoma, including targeted therapies and immunotherapies. However, no biomarkers are available for the prediction of the therapeutic response. In this context, several studies have tried to understand the diagnostic, prognostic and therapeutic potential of MMP-9 in melanoma patients by performing clinical trials with synthetic MMPs inhibitors. Therefore, MMP-9 may be considered a promising molecule for the management of melanoma patients due to its role as a biomarker and therapeutic target.

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Section: Introductionmentioning

confidence: 99%

Functional Roles of Matrix Metalloproteinases and Their Inhibitors in Melanoma

Napoli

Scuderi

Gattuso

et al. 2020

Cells

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“…In each of these cases, the increase in MMP-14 correlates with remodeling of the tissue and/or vasculature that can lead to increased morbidity and rates of mortality. While MMP-14 is an attractive therapeutic target, attempts at inhibiting MMPs directly have failed spectacularly during clinical trials [ 45 ]. Establishing a causative link between inflammation and MMP-14 expression thus opens the door for development of therapeutics which may disrupt this signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 increases matrix metalloproteinase-14 (MMP-14) levels via down-regulation of p53 to drive cancer progression

et al. 2016

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Matrix metalloproteinases (MMPs) play critical roles in cancer invasion and metastasis by digesting basement membrane and extracellular matrix (ECM). Much attention has focused on the enzymatic activities of MMPs; however, the regulatory mechanism of MMP expression remains elusive. By employing bioinformatics analysis, we identified a potential p53 response element within the MMP-14 promoter. Experimentally, we found that p53 can repress MMP-14 promoter activity, whereas deletion of this p53 response element abrogated this effect. Furthermore, we found that p53 expression decreases MMP-14 mRNA and protein levels and attenuates MMP-14-mediated cellular functions. Additional promoter analysis and chromatin immunoprecipitation studies identified a mechanism of regulation of MMP-14 expression by which p53 and transcription factor Sp1 competitively bind to the promoter. As the correlation between inflammation and cancer aggressiveness is well described, we next sought to evaluate if inflammatory cytokines could differentially affect p53 and MMP-14 levels. We demonstrate that interleukin-6 (IL-6) down-regulates p53 protein levels and thus results in a concomitant increase in MMP-14 expression, leading to enhanced cancer cell invasion and metastasis. Our data collectively indicate a novel mechanism of regulation of MMP-14 by a cascade of IL-6 and p53, demonstrating that the tumor microenvironment directly stimulates molecular changes in cancer cells to drive an invasive phenotype.

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“…The numerous structures that characterize MMPs allow them to perform multiple roles that influence various processes such as cell behavior, apoptosis, and cell proliferation. MMPs have been found to promote tumor progression by degrading surrounding tissues, modulating growth factors and membrane receptors, as well as inflammatory proteins, adhesion molecules, and chemo-attractive proteins, according to oncological studies [110][111][112]. MMPs are also involved in the alteration of the ECM of the skin.…”

Section: Matrix Metalloproteinasesmentioning

confidence: 99%

Role of Biomarkers in the Integrated Management of Melanoma

Naik¹

2021

Disease Markers

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Melanoma, which is an aggressive skin cancer, is currently the fifth and seventh most common cancer in men and women, respectively. The American Cancer Society reported that approximately 106,110 new cases of melanoma were diagnosed in the United States in 2021, with 7,180 people dying from the disease. This information could facilitate the early detection of possible metastatic lesions and the development of novel therapeutic techniques for melanoma. Additionally, early detection of malignant melanoma remains an objective of melanoma research. Recently, melanoma treatment has substantially improved, given the availability of targeted treatments and immunotherapy. These developments have highlighted the significance of identifying biomarkers for prognosis and predicting therapy response. Biomarkers included tissue protein expression, circulating DNA detection, and genetic alterations in cancer cells. Improved diagnostic and prognostic biomarkers are becoming increasingly relevant in melanoma treatment, with the development of newer and more targeted treatments. Here, the author discusses the aspects of biomarkers in the real-time management of patients with melanoma.

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Therapeutics Targeting Matrix Metalloproteinases

Cited by 4 publications

References 90 publications

Functional Roles of Matrix Metalloproteinases and Their Inhibitors in Melanoma

Functional Roles of Matrix Metalloproteinases and Their Inhibitors in Melanoma

Interleukin-6 increases matrix metalloproteinase-14 (MMP-14) levels via down-regulation of p53 to drive cancer progression

Role of Biomarkers in the Integrated Management of Melanoma

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