Abstract
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.
Keywords:
Bcl-2 phosphorylation; colorectal cancer; paxillin; prognosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzimidazoles / therapeutic use
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Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
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Cell Line, Tumor
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / mortality
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Colorectal Neoplasms / pathology*
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Dasatinib / therapeutic use
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Enzyme Activation
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Enzyme Induction
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Extracellular Signal-Regulated MAP Kinases / physiology
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Heterografts
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Humans
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Kaplan-Meier Estimate
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Leupeptins / therapeutic use
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Lung Neoplasms / metabolism
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Lung Neoplasms / secondary
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Matrix Metalloproteinase 2 / biosynthesis
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Matrix Metalloproteinase 2 / genetics
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Mice
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Mice, Nude
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Neoplasm Invasiveness
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Paxillin / physiology*
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Phosphorylation
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Proportional Hazards Models
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Protein Processing, Post-Translational*
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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RNA Interference
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RNA, Small Interfering / genetics
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Recombinant Fusion Proteins / metabolism
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Sulfonamides / therapeutic use
Substances
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AZD 6244
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BCL2 protein, human
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Benzimidazoles
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Bridged Bicyclo Compounds, Heterocyclic
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Leupeptins
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Neoplasm Proteins
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PXN protein, human
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Paxillin
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Sulfonamides
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Extracellular Signal-Regulated MAP Kinases
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MMP2 protein, human
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Matrix Metalloproteinase 2
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venetoclax
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Dasatinib
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde