azd-6244 has been researched along with benzyloxycarbonylleucyl-leucyl-leucine-aldehyde* in 2 studies
2 other study(ies) available for azd-6244 and benzyloxycarbonylleucyl-leucyl-leucine-aldehyde
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Paxillin promotes colorectal tumor invasion and poor patient outcomes via ERK-mediated stabilization of Bcl-2 protein by phosphorylation at Serine 87.
Stabilization of Bcl-2 protein by paxillin (PXN)-mediated ERK activation was recently reported to cause an unfavorable response to 5-Fluorouracil-based chemotherapy. Here, we present evidence from cell and animal models to demonstrate that stabilization of Bcl-2 protein by phosphorylation at Serine 87 (pBcl-2-S87) via PXN-mediated ERK activation is responsible for cancer cell invasiveness and occurs via upregulation of MMP2 expression. Immunostainings of 190 tumors resected from colorectal cancer patients indicated that PXN expression was positively correlated with Bcl-2, pBcl-2-S87, and MMP2 expression. A positive correlation of pBcl-2-S87 with Bcl-2 and MMP2 was also observed in this study population. Patients with high PXN, Bcl-2, pBcl-2-S87, and MMP2 had poor overall survival (OS) and shorter relapse free survival (RFS). In conclusion, PXN promotes Bcl-2 phosphorylation at Serine 87 via PXN-mediated ERK activation, and its stabilization associated with increased tumor formation efficacy in mice and poor patient outcome in colorectal cancer patients. Topics: Animals; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Colorectal Neoplasms; Dasatinib; Enzyme Activation; Enzyme Induction; Extracellular Signal-Regulated MAP Kinases; Heterografts; Humans; Kaplan-Meier Estimate; Leupeptins; Lung Neoplasms; Matrix Metalloproteinase 2; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Proteins; Paxillin; Phosphorylation; Proportional Hazards Models; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-bcl-2; Recombinant Fusion Proteins; RNA Interference; RNA, Small Interfering; Sulfonamides | 2015 |
Small molecule inhibition of the steroid receptor coactivators, SRC-3 and SRC-1.
Overexpression of steroid receptor coactivator (SRC)-1 and SRC-3 is associated with cancer initiation, metastasis, advanced disease, and resistance to chemotherapy. In most of these cases, SRC-1 and SRC-3 have been shown to promote tumor cell growth by activating nuclear receptor and multiple growth factor signaling cascades that lead to uncontrolled tumor cell growth. Up until now, most targeted chemotherapeutic drugs have been designed largely to block a single pathway at a time, but cancers frequently acquire resistance by switching to alternative growth factor pathways. We reason that the development of chemotherapeutic agents against SRC coactivators that sit at the nexus of multiple cell growth signaling networks and transcriptional factors should be particularly effective therapeutics. To substantiate this hypothesis, we report the discovery of 2,2'-bis-(Formyl-1,6,7-trihydroxy-5-isopropyl-3-methylnaphthalene (gossypol) as a small molecule inhibitor of coactivator SRC-1 and SRC-3. Our data indicate that gossypol binds directly to SRC-3 in its receptor interacting domain. In MCF-7 breast cancer cells, gossypol selectively reduces the cellular protein concentrations of SRC-1 and SRC-3 without generally altering overall protein expression patterns, SRC-2, or other coactivators, such as p300 and coactivator-associated arginine methyltransferase 1. Gossypol reduces the concentration of SRC-3 in prostate, lung, and liver cancer cell lines. Gossypol inhibits cell viability in the same cancer cell lines where it promotes SRC-3 down-regulation. Additionally, gossypol sensitizes lung and breast cancer cell lines to the inhibitory effects of other chemotherapeutic agents. Importantly, gossypol is selectively cytotoxic to cancer cells, whereas normal cell viability is not affected. This data establish the proof-of-principle that, as a class, SRC-1 and SRC-3 coactivators are accessible chemotherapeutic targets. Given their function as integrators of multiple cell growth signaling systems, SRC-1/SRC-3 small molecule inhibitors comprise a new class of drugs that have potential as novel chemotherapeutics able to defeat aspects of acquired cancer cell resistance mechanisms. Topics: Animals; Antineoplastic Agents; Benzimidazoles; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Synergism; Estrogen Receptor alpha; Gossypol; Humans; Inhibitory Concentration 50; Leupeptins; Male; MAP Kinase Kinase 1; Mice; Nuclear Receptor Coactivator 1; Nuclear Receptor Coactivator 2; Nuclear Receptor Coactivator 3; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Binding; Protein Interaction Domains and Motifs; Protein Stability; Transcription, Genetic | 2011 |