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.
['Huang|Chi-Chou|CC|', 'Wu|De-Wei|DW|', 'Lin|Po-Lin|PL|', 'Lee|Huei|H|']
D000818:Animals D001562:Benzimidazoles D019086:Bridged Bicyclo Compounds, Heterocyclic D045744:Cell Line, Tumor D015179:Colorectal Neoplasms D000069439:Dasatinib D004789:Enzyme Activation D004790:Enzyme Induction D048049:Extracellular Signal-Regulated MAP Kinases D064593:Heterografts D006801:Humans D053208:Kaplan-Meier Estimate D007976:Leupeptins D008175:Lung Neoplasms D020778:Matrix Metalloproteinase 2 D051379:Mice D008819:Mice, Nude D009361:Neoplasm Invasiveness D009363:Neoplasm Proteins D051419:Paxillin D010766:Phosphorylation D016016:Proportional Hazards Models D011499:Protein Processing, Post-Translational D019253:Proto-Oncogene Proteins c-bcl-2 D034622:RNA Interference D034741:RNA, Small Interfering D011993:Recombinant Fusion Proteins D013449:Sulfonamides
paxillin colorectal cancer Bcl-2 phosphorylation prognosis