title: Paxillin promotes colorectal tumor invasion and poor patient outcomes via ERK-mediated stabilization of Bcl-2 protein by phosphorylation at Serine 87.
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.
authors.affiliation: School of Medicine, Chung Shan Medical University, Taichung, Taiwan.|Department of Surgery, Division of Colon and Rectum, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Chi-Chou
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
authors.forename: De-Wei
authors.initials: DW
authors.lastname: Wu
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Lin
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
authors.forename: Huei
authors.initials: H
authors.lastname: Lee
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D000069439:Dasatinib / Q000627:therapeutic use; D004789:Enzyme Activation; D004790:Enzyme Induction; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D007976:Leupeptins / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051419:Paxillin / Q000502:physiology*; D010766:Phosphorylation; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use
chemical_list: C517975:AZD 6244; C000595707:BCL2 protein, human; D001562:Benzimidazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007976:Leupeptins; D009363:Neoplasm Proteins; C496061:PXN protein, human; D051419:Paxillin; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D048049:Extracellular Signal-Regulated MAP Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579720:venetoclax; D000069439:Dasatinib; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Bcl-2 phosphorylation; colorectal cancer; paxillin; prognosis
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