The TIMPs tango with MMPs and more in the central nervous system

Crocker, Stephen J.; Pagenstecher, Axel; Campbell, Iain L.

doi:10.1002/jnr.10836

Cited by 123 publications

(114 citation statements)

References 92 publications

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“…The results of the present study indicated that the ability of ILL to inhibit the invasion and migration of A549 cells might be associated with reduced protein expression and secretion of MMP-2 in lung cancer cells. TIMP-2 is the endogenous inhibitor of MMP-2, and can combine extra cellularly with MMP-2 to inhibit MMP-2 activity (40,41). However, the present study did not observe any significant increase in TIMP-2 protein expression brought about by ILL (data not shown).…”

Section: Discussioncontrasting

confidence: 78%

Anti-metastatic effects of isolinderalactone via the inhibition of MMP-2 and up regulation of NM23-H1 expression in human lung cancer A549 cells

et al. 2018

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Abstract. Metastatic lung cancer is a leading cause of mortality and has a mortality rate of ≥90%. Isolinderalactone (ILL) is a sesquiterpene lactone compound that has been used in traditional Chinese medicine. Research has demonstrated that ILL has anti-inflammatory and anti-proliferative properties; however, to the best of our knowledge, studies investigating whether ILL can inhibit lung cancer cell metastasis have not been conducted. In the present study, 1-10 µM ILL was applied in the culturing of the A549 lung cancer cell line to investigate the effects of ILL on the invasion and migration of lung cancer cells, including whether the possible mechanisms of ILL are associated with the expression of matrix metalloproteinase (MMP)-2 and NME/NM23 nucleoside diphosphate kinase 1 (NM23-H1) genes. The results of the present study indicated that ILL inhibited the invasion and migration of the A549 cancer cells and exhibited a dose-response association. ILL also significantly inhibited the protein expression and activity of MMP-2 (P<0.05), exhibiting a trend similar to that of its invasion-and migration-associated properties. Further research revealed that ILL significantly increased the expression of NM23-H1 protein and inhibited the expression of β-catenin protein (P<0.05). The results of the present study is, to the best of our knowledge, the first to confirm that ILL can inhibit the invasion and migration of A549 cancer cells, with the possible mechanisms potentially involving the inhibition of MMP-2 and β-catenin protein expression resulting from the up regulation of NM23-H1 expression. IntroductionCancer is a leading cause of mortality; ~8.2 million people worldwide succumbed to cancer-associated mortality in 2012, with lung cancer accounting for ~1.59 million cases of mortality, or ~20% of the total (1). Lung cancer cell metastasis is a primary cause of mortality and those that experience it have a mortality rate of ≥90% (2). When it metastasizes, lung cancer has a 95% chance of affecting local lymph nodes and an 80% chance of affecting other organs (3,4). Thus, in clinical terms, the overall 5-year survival rate from the time of diagnosis to mortality for patients with lung cancer undergoing treatment is only 10-15% (5). Cancer cell metastasis is a complex multistep process involving invasion and migration (6-8). Matrix metalloproteinases (MMPs) are zinc/calcium-dependent endopeptidases involved in the degradation of the extracellular matrix, two examples of which are MMP-2 and -9 (7,9). MMP-2 is a notable factor in the development of tumor metastasis (7,10). MMP-2 is highly expressed in malignant tumors and serves a key role in cancer invasion and angiogenesis (7,11). The inhibition of MMP-2 is, therefore, an effective strategy for preventing tumor cell metastasis (11,12). The NME/NM23 nucleoside diphosphate kinase 1 (NM23) gene was first identified in the murine melanoma cell line exhibiting high metastatic activity; increasing the expression of this gene may also reduce the metastatic activity of tumor cel...

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Section: Discussioncontrasting

confidence: 78%

Anti-metastatic effects of isolinderalactone via the inhibition of MMP-2 and up regulation of NM23-H1 expression in human lung cancer A549 cells

et al. 2018

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“…Because MMP activity contributes to the damage that occurs after ischemia, TIMP neuroprotection is likely to occur through classical MMP inhibition. However, TIMPs have a wide variety of other functions, not all of which are attributed to MMP blockade, such as apoptosis/survivalmodulating mechanisms (50). These pathways are involved in cerebral ischemia (51,52).…”

Section: Discussionmentioning

confidence: 99%

Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia

Baker

Sica

Work

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Despite advances in imaging, understanding the underlying pathways, and clinical translation of animal models of disease there remains an urgent need for therapies that reduce brain damage after stroke and promote functional recovery in patients. Blocking oxidant radicals, reducing matrix metalloproteinase-induced neuronal damage, and use of stem cell therapy have been proposed and tested individually in prior studies. Here we provide a comprehensive integrative management approach to reducing damage and promoting recovery by combining biological therapies targeting these areas. In a rat model of transient cerebral ischemia (middle cerebral artery occlusion) gene delivery vectors were used to overexpress tissue inhibitor of matrix metalloproteinase 1 and 2 (TIMP1 and TIMP2) 3 days before ischemia. After occlusion, autologous bone marrow cells alone or in combination with agents to improve NO bioavailability were administered intraarterially. When infarct size, BrdU incorporation, and motor function recovery were determined in the treatment groups the largest beneficial effect was seen in rats receiving the triple combined therapy, surpassing effects of single or double therapies. Our study highlights the utility of combined drug, gene, and cell therapy in the treatment of stroke.

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“…MMP-3 has been associated with pathogenesis of a number of diseases such as Alzheimer disease, Parkinson disease, stroke, brain trauma, neuroinflammation, multiple sclerosis, glioma, and arthritis (7)(8)(9)(10). Although the enzyme was previously thought to be active only outside the cell, we have recently reported its novel, additional role inside the cell.…”

mentioning

confidence: 95%

Matrix Metalloproteinase-3 Is Increased and Participates in Neuronal Apoptotic Signaling Downstream of Caspase-12 during Endoplasmic Reticulum Stress

Kim

Shin

Choi

et al. 2010

Journal of Biological Chemistry

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Although endoplasmic reticulum (ER) stress-induced apoptosis has been associated with pathogenesis of neurodegenerative diseases, the cellular components involved have not been well delineated. The present study shows that matrix metalloproteinase (MMP)-3 plays a role in the ER stress-induced apoptosis. ER stress induced by brefeldin A (BFA) or tunicamycin (TM) increases gene expression of MMP-3, selectively among various MMP subtypes, and the active form of MMP-3 (actMMP-3) in the brain-derived CATH.a cells. Pharmacological inhibition of enzyme activity, small interference RNA-mediated gene knockdown, and gene knock-out of MMP-3 all provide protection against ER stress. MMP-3 acts downstream of caspase-12, because both pharmacological inhibition and gene knockdown of caspase-12 attenuate the actMMP-3 increase, but inhibition and knock-out of MMP-3 do not alter caspase-12. Furthermore, independently of the increase in the protein level, the catalytic activity of MMP-3 enzyme can be increased via lowering of its endogenous inhibitor protein TIMP-1. Caspase-12 causes liberation of MMP-3 enzyme activity by degrading TIMP-1 that is already bound to actMMP-3. TIMP-1 is decreased in response to ER stress, and TIMP-1 overexpression leads to cell protection and a decrease in MMP-3 activity. Taken together, actMMP-3 protein level and catalytic activity are increased following caspase-12 activation during ER stress, and this in turn plays a role in the downstream apoptotic signaling in neuronal cells. MMP-3 and TIMP-1 may therefore serve as cellular targets for therapy against neurodegenerative diseases. The endoplasmic reticulum (ER)2 is the organelle responsible for proper synthesis and folding of proteins as well as maintenance of intracellular calcium homeostasis. Various cellular stresses cause disruption of normal ER functions, leading to ER stress, and excessive and prolonged ER stress leads to accumulation of misfolded and/or unfolded proteins, and ultimately apoptosis (1).Neurons are particularly vulnerable to ER stress, and ample evidence exists in the literature that links ER stress with neurodegeneration (2-4). Therefore, identification of cellular components and elucidation of the sequence of events following ER stress in neuronal cells would be of great importance in understanding the mechanism of neurodegeneration. The molecular connection between the ER stress response and apoptotic signaling, however, is not clearly understood. Although caspase-12, residing outside of ER membrane, has been shown to be specifically involved in the apoptotic signaling that results from ER stress (5, 6), the exact mechanism by which this occurs has not been elucidated and immediate downstream targets of caspase-12 remain to be identified.Matrix metalloproteinase (MMP)-3 belongs to a family of MMP enzymes known to participate in degradation of components of the extracellular matrix. MMP-3 has been associated with pathogenesis of a number of diseases such as Alzheimer disease, Parkinson disease, stroke, brain trauma, neuroinfl...

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The TIMPs tango with MMPs and more in the central nervous system

Cited by 123 publications

References 92 publications

Anti-metastatic effects of isolinderalactone via the inhibition of MMP-2 and up regulation of NM23-H1 expression in human lung cancer A549 cells

Anti-metastatic effects of isolinderalactone via the inhibition of MMP-2 and up regulation of NM23-H1 expression in human lung cancer A549 cells

Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia

Matrix Metalloproteinase-3 Is Increased and Participates in Neuronal Apoptotic Signaling Downstream of Caspase-12 during Endoplasmic Reticulum Stress

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