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)

Inorganic arsenic is a human carcinogen that likely targets the prostate. Chronic arsenic exposure malignantly transforms the RWPE-1 human prostate epithelial line to chronic arsenic exposed-prostate epithelial (CAsE-PE) cells, and a derivative normal prostate stem cell (SC) line, WPE-stem to arsenic-cancer SCs (As-CSCs). The KRAS oncogene is highly overexpressed in CAsE-PE cells and activation precedes transformation, inferring mechanistic significance. As-CSCs also highly overexpress KRAS. Thus, we hypothesize KRAS activation is key in causing and maintaining an arsenic-induced malignant phenotype, and hence, KRAS knockdown (KD) may reverse this malignant phenotype. RNA interference using shRNAmirs to obtain KRAS KD was used in CAsE-PE and As-CSC cells. Cells analyzed 2 weeks post transduction showed KRAS protein decreased to 5% of control after KD, confirming stable KD. KRAS KD decreased phosphorylated ERK, indicating inhibition of RAS/ERK signaling, a proliferation/survival pathway activated with arsenic transformation. Secreted metalloproteinase (MMP) activity was increased by arsenic-induced malignant transformation, but KRAS KD from 4 weeks on decreased secreted MMP-9 activity by 50% in As-CSCs. Colony formation, a characteristic of cancer cells, was decreased in both KRAS KD transformants. KRAS KD also decreased the invasive capacity of both cell types. KRAS KD decreased proliferation in As-CSCs, consistent with loss of rapid tumor growth. Genes predicted to impact cell proliferation (eg, Cyclin D1, p16, and p21) changed accordingly in both KD cell types. Thus, KRAS silencing impacts aspects of arsenic-induced malignant phenotype, inducing loss of many typical cancer characteristics particularly in As-CSCs.
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PMID:Silencing KRAS overexpression in arsenic-transformed prostate epithelial and stem cells partially mitigates malignant phenotype. 2527 66

The present research has been carried out to elicit the mechanism of antiangiogenic activity of a fusion peptide P2. Peptide P2 was designed by the connection of a heptapeptide MMP inhibitor to ES-2, a fragment of Endostatin. In a previous study, P2 demonstrated strong antiangiogenic and antitumor effect, and the current work explains the antiangiogenic mechanism of P2 through endothelial cell proliferation and apoptosis. In our study, it was shown that P2 inhibited HUVECs proliferation at a low serum concentration and this effect might be achieved through arresting cell cycle by decreasing the expression level of Cyclin D1. In addition, P2 was found to induce apoptosis of HUVECs. Using Western blot, it was indicated that P2 induced the cleavage of Caspase-3, the hallmark protease of apoptosis. The activation and expression of the upstream regulator Caspase-9 can also be affected by P2 treatment. Furthermore, P2 reduced the protein level of antiangiogenic factors Bcl-xL and Bcl-2. These results revealed that P2 regulates endothelial cell apoptosis through intrinsic apoptotic pathway.
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PMID:A fusion antitumor peptide regulates proliferation and apoptosis of endothelial cells. 2979 30