Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The roles of the protein-serine/threonine kinase, Akt1, in signaling pathways associated with cell motility and extracellular matrix invasion were examined in the immortalized mouse mammary epithelial cell line, COMMA-1D. COMMA-1D cells were engineered to express the avian leukosis subtype A receptor, tv-a, to permit infection by recombinant avian leukosis virus produced by the replication-competent avian splice vector, RCAS. COMMA-1D/tv-a cells transduced with RCAS/v-akt, but not RCAS/Akt1, formed anchorage-independent colonies in soft agar; however, cells overexpressing either v-akt or Akt1 became highly invasive when grown on the ECM, Matrigel. Zymography of extracellular protease activity shed into the medium by COMMA-1D/Akt1 or COMMA-1D/v-akt cells revealed elevated gelatinase activity that was confirmed to be matrix metalloproteinase-2 (MMP-2; gelatinase A) by Western blotting and immunoprecipitation-zymography. The MMP inhibitor, BB-94, blocked MMP-2 activity and invasion associated with Akt1- and v-akt-expressing cells. The proteasome inhibitor, lactacystin, markedly increased MMP-2 levels and invasion in control cells but not in Akt1- and v-akt-expressing cells. These results suggest that the invasive behavior of mammary epithelial cells induced by Akt1 is associated with increased MMP-2 expression that may result from inhibition of MMP-2 degradation by the proteasome pathway.
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PMID:Akt1 induces extracellular matrix invasion and matrix metalloproteinase-2 activity in mouse mammary epithelial cells. 1160 7

MG132 as a proteasome inhibitor can induce apoptotic cell death through formation of reactive oxygen species (ROS). In this study, we investigated the effects of MAPK (MEK, JNK or p38) inhibitors on MG132-induced HeLa cell death in relation to ROS and glutathione (GSH). MG132-induced cell growth inhibition and apoptosis in HeLa cells, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). MG132 increased ROS level including O(2)(*-) and GSH depleted cell number in HeLa cells. All the MAPK inhibitors slightly enhanced the cell growth inhibition but did not intensify apoptosis in MG132-treated HeLa cells. Each MAPK inhibitor differentially changed the levels of ROS and GSH content in MG132-treated cells. In conclusion, MAPK inhibitors partially influence apoptosis, ROS and GSH levels in MG132-treated HeLa cells.
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PMID:The effects of MAPK inhibitors on a proteasome inhibitor, MG132-induced HeLa cell death in relation to reactive oxygen species and glutathione. 1985 51

Carbobenzoxy-Leu-Leu-leucinal (MG132) as a proteasome inhibitor has been shown to induce apoptotic cell death through formation of reactive oxygen species (ROS). In the present study, we evaluated the effects of MG132 on the growth of A549 lung cancer cells in relation to cell growth, ROS and glutathione (GSH) levels. Treatment with MG132 inhibited the growth of A549 cells with an IC(50) of approximately 20 microM at 24 hours. DNA flow cytometric analysis indicated that 0.5 approximately 30 microM MG132 induced a G1 phase arrest of the cell cycle in A549 cells. Treatment with 10 or 30 microM MG132 also induced apoptosis, as evidenced by sub-G1 cells and annexin V staining cells. This was accompanied by the loss of mitochondrial membrane potential (MMP; Delta psi m). The intracellular ROS levels including O(2) (*-) were strongly increased in 10 or 30 microM MG132-treated A549 cells but were down-regulated in 0.1, 0.5 or 1 microM MG132-treated cells. Furthermore, 10 or 30 microM MG132 increased mitochondrial O(2) (*- ) level but 0.1, 0.5 or 1 microM MG132 decreased that. In addition, 10 or 30 microM MG132 induced GSH depletion in A549 cells. In conclusion, MG132 inhibited the growth of human A549 cells via inducing the cell cycle arrest as well as triggering apoptosis, which was in part correlated with the changes of ROS and GSH levels. Our present data provide important information on the anti-growth mechanisms of MG132 in A549 lung cancer cells in relation to ROS and GSH.
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PMID:MG132 as a proteasome inhibitor induces cell growth inhibition and cell death in A549 lung cancer cells via influencing reactive oxygen species and GSH level. 2005 4

MG132 as a proteasome inhibitor has been shown to induce apoptotic cell death through the formation of reactive oxygen species (ROS). Here, we evaluated the effects of MG132 on the growth of endothelial cells (ECs), especially calf pulmonary artery endothelial cells (CPAECs), in relation to cell death, ROS, and glutathione (GSH) levels. MG132 dose dependently inhibited the growth of CPAEC and human umbilical vein endothelial cells (HUVECs) at 24 hours. MG132 also induced apoptotic cell death in CPAEC, which were accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). MG132 increased ROS levels, including O(2)(*-) in CPAEC, but not in HUVEC. MG132 also dose dependently increased GSH-depleted cells in both ECs. N-acetyl-cysteine (NAC; a well-known antioxidant) reduced ROS levels in MG132-treated CPAEC with the slight prevention of cell death and GSH depletion. Buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) increased ROS levels and decreased GSH levels in MG132-treated CPAEC without the enhancement of cell death. In conclusion, MG132 inhibited the growth of ECs, especially CPAEC. The changes of ROS and GSH levels by MG132 partially affect CPAEC death.
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PMID:Reactive oxygen species and glutathione level changes by a proteasome inhibitor, MG132, partially affect calf pulmonary arterial endothelial cell death. 2008 36

The proteasome inhibitor MG132 has been shown to induce apoptotic cell death through the formation of reactive oxygen species (ROS). Here, we evaluated the effects of MG132 on the growth and death of As4.1 juxtaglomerular cells in relation to ROS and glutathione (GSH) levels. MG132 inhibited the growth of As4.1 cells with an IC(50) of approximately 0.3-0.4microM at 48h and induced cell death, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)), Bcl-2 decrease, activation of caspase-3 and -8, and PARP cleavage. MG132 increased intracellular ROS levels including O(2)(-) and GSH depleted cell numbers. N-acetyl cysteine (NAC, a well-known antioxidant) significantly decreased ROS level and GSH depleted cell numbers in MG132-treated As4.1 cells, along with the prevention of cell growth inhibition, cell death and MMP (DeltaPsi(m)) loss. NAC also decreased the caspase-3 activity of MG132. l-Buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) or diethyldithiocarbamate (DDC; an inhibitor of Cu/Zn-SOD) did not affect cell growth, death, ROS and GSH levels in MG132-treated As4.1 cells. Conclusively, MG132 reduced the growth of As4.1 cells via apoptosis. The changes of ROS and GSH by MG132 were involved in As4.1 cell growth and death.
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PMID:The changes of reactive oxygen species and glutathione by MG132, a proteasome inhibitor affect As4.1 juxtaglomerular cell growth and death. 2010 Apr 72

The inhibition of proteasome function has emerged as a useful strategy to maneuver apoptosis. In the present study, we evaluated the effects of MG132 as a proteasome inhibitor on the growth of Calu-6 lung cancer cells in relation to the cell cycle, cell death, reactive oxygen species (ROS) and glutathione (GSH) levels. MG132 dose-dependently inhibited the growth of Calu-6 cells at 24h. DNA flow cytometric analysis indicated that 1-30 microM MG132 induced an S phase arrest in Calu-6 cells. MG132 also induced apoptosis, which was accompanied by the loss of mitochondrial membrane potential (MMP; Deltapsi(m)). The pan-caspase inhibitor (Z-VAD) significantly rescued Calu-6 cells from MG132-induced cell death. The intracellular ROS levels including O(2)(-) were increased in MG132-treated Calu-6 cells. MG132 also increased GSH-depleted cell numbers in Calu-6 cells. Z-VAD significantly decreased O(2)(-) levels and GSH-depleted cell numbers in MG132-treated Calu-6 cells. In conclusion, MG132 inhibited the growth of Calu-6 cells via apoptosis and GSH depletion.
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PMID:MG132, a proteasome inhibitor decreased the growth of Calu-6 lung cancer cells via apoptosis and GSH depletion. 2014 58

MG132 as a proteasome inhibitor has been shown to induce apoptotic cell death through formation of reactive oxygen species (ROS). Here, we investigated the effects of N-acetyl cysteine (NAC; a well-known antioxidant), L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) or diethyldithiocarbamate (DDC; an inhibitor of Cu/Zn-SOD) on MG132-treated Calu-6 or A549 lung cancer cells in relation to cell growth, ROS and GSH levels. MG132 inhibited the growth of Calu-6 and A549 cells at 24 h. MG132 induced apoptosis in both cell lines, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsim). ROS levels including O(2)(.-) were increased in both MG132-treated lung cells. MG132 also induced GSH depletion in both lung cell types. Treatment with 10 microM BSO or 1 microM DDC affected ROS and GSH levels in MG132-treated Calu-6 cells. However, these changes did not influence cell growth and death in the cells. NAC prevented cell growth inhibition and death in MG132-treated lung cells, which was accompanied by decreased ROS, but not by decreased GSH depletion. In conclusion, the changes of ROS and GSH by MG132, NAC, BSO or DDC were partially related to cell growth and death in the lung cancer cell lines Calu-6 and A549.
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PMID:The effects of N-acetyl cysteine on the MG132 proteasome inhibitor-treated lung cancer cells in relation to cell growth, reactive oxygen species and glutathione. 2019 16

Resistance to drug treatments underlies the high lethality of pancreatic ductal adenocarcinoma. Along with others, we have recently identified that proteasome inhibition is a promising therapeutic option in this highly refractory disease. The pleiotropic effects of proteasome inhibition include the activation of apoptotic signaling pathways and also antiapoptotic signaling pathways such as EGFR, AKT and the MAP kinases that reduce the apoptotic potential of this class of drug. In this study, we sought to determine the mechanism behind the activation of EGFR in response to proteasome inhibition in pancreatic cancer cells. We found that the second-generation proteasome inhibitor NPI-0052 induced the mRNA transcription of several EGFR family ligands (EGF, HB-EGF and epiregulin), however only increases in HB-EGF were detected at the protein level. Using both pharmacological inhibitors and lentiviral-mediated shRNA knockdown of EGFR ligand expression, we discovered that ligand cleavage by MMP/ADAMs and HB-EGF expression is required for activation of EGFR in response to proteasome inhibition. Furthermore, we discover that induction of HB-EGF is dependent on reactive oxygen species and p38-MAPK signaling but not ERK and that the transcription factor SP-1 is involved in NPI-0052-induced HB-EGF transcription. Together, these results indicate that stress signaling leading to induction of HB-EGF expression and increases in MMP/ADAM-dependent HB-EGF cleavage are responsible for proteasome inhibitor-induced activation of EGFR in pancreatic cancer cells.
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PMID:Activation of EGFR by proteasome inhibition requires HB-EGF in pancreatic cancer cells. 2020 58

MG132, as a proteasome inhibitor, can induce apoptotic cell death through formation of reactive oxygen species (ROS). In this study, we investigated the effects of MAPK (MEK, JNK, and p38) inhibitors on MG132-treated A549 lung cancer cells in relation to cell growth, cell death, ROS, and glutathione (GSH) levels. Treatment with 10 microM MG132 inhibited the growth of A549 cells at 24 h. MG132 also induced apoptosis, which was accompanied by the loss of mitochondrial membrane potential (MMP; deltapsi(m)). ROS were not increased in MG132-treated A549 cells. MG132 increased GSH-depleted cell numbers and decreased GSH levels. MEK and JNK inhibitors did not strongly affect cell growth, cell death, ROS, and GSH levels in MG132-treated A549 cells. In contrast, p38 inhibitor reduced cell growth inhibition, apoptosis, and MMP (deltapsi(m)) loss by MG132. However, p38 inhibitor did not change ROS level and GSH content. In conclusion, MG132 inhibited the growth of A549 cells via apoptosis without formation of ROS. Treatment with p38 inhibitor rescued some cells from MG132-induced apotposis, which was not affected by ROS and GSH level changes.
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PMID:The attenuation of MG132, a proteasome inhibitor, induced A549 lung cancer cell death by p38 inhibitor in ROS-independent manner. 2037 32

The proteasome inhibitor MG132 has been shown to induce apoptotic cell death through the formation of reactive oxygen species (ROS). Here, we investigated the molecular mechanisms of MG132 in As4.1 juxtaglomerular cell death in relation to apoptosis and levels of ROS and glutathione (GSH). MG132 inhibited the growth of As4.1 cells with an IC(50) of approximately 0.3-0.4 microM at 48 h and induced cell death, accompanied by the loss of mitochondrial membrane potential (MMP; Psi(m)), Bcl-2 decrease, activations of caspase-3 and caspase-8, and PARP cleavage. MG132 increased intracellular ROS levels and GSH-depleted cell numbers. However, caspase inhibitors, especially Z-VAD (pan-caspase inhibitor) intensified cell growth inhibition, cell death, MMP (Psi(m)) loss, and Bcl-2 decrease in MG132-treated As4.1 cells. Z-VAD also slightly intensified increases in ROS levels and GSH depletion in MG132-treated As4.1 cells. In conclusion, MG132 reduced the growth of As4.1 cells via caspase-independent apoptosis. The changes in ROS and GSH levels by MG132 and caspase inhibitors partially influenced the growth inhibition and death of As4.1 cells.
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PMID:Proteasome inhibitor MG132 reduces growth of As4.1 juxtaglomerular cells via caspase-independent apoptosis. 2044 26


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