title: Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer.
abstract: 5-Fluorouracil (5-FU) is chemotherapeutic agent widely used for the treatment of colorectal cancer. Unfortunately, advanced colorectal cancer is often resistance to such chemotherapy and poor outcome. An adaptor protein paxillin (PXN) is phosphorylated at Y31/Y118 (pPXN-Y31/Y118) by Src contributes to cell mobility and Ser (S)272 of PXN in LD4 domain is important to the interaction between PXN and Bcl-2. We thus hypothesized that pPXN-Y31/Y118 may be required for Bcl-2 protein stability via PXN interacting with Bcl-2 to confer 5-FU resistance in colorectal cancer. Mechanistically, pPXN-S272 is phosphorylated through pPXN-Y31/Y118-mediated p21 protein-activated kinase 1 (PAK1) activation and pPXN-S272 is required for PXN to interact with Bcl-2. The interaction between PXN and Bcl-2 is essential for Bcl-2 protein stability through phosphorylation of Bcl-2 at S87 (pBcl-2-S87) by pPXN-Y31/Y118-mediated ERK activation. An increase in Bcl-2 expression by PXN is responsible for resistance to 5-FU. The resistance to 5-FU can be abolished by inhibitor of Src and PAK1 or Bcl-2 antagonist in cell and animal models. Among patients, Bcl-2 expression is positively correlated with expression of PXN and pPXN-S272, respectively. Patients with high PXN/high Bcl-2 or high pPXN-S272/high Bcl-2 tumors are commonly to have an unfavorable response to 5-FU-based chemotherapy, compared with patients who have high PXN, high pPXN-S272 or high Bcl-2 tumors alone. Therefore, we suggest that Src, PAK1 or Bcl-2 inhibitor may potentially overcome the resistance of 5-FU-based chemotherapy and consequently to improve outcomes in patients with PXN/Bcl-2 and pPXN-S272/Bcl-2-positive tumors.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: D-W
authors.initials: DW
authors.lastname: Wu
authors.affiliation: 1] School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan [2] Division of Colon and Rectum, Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: C-C
authors.initials: CC
authors.lastname: Huang
authors.affiliation: 1] School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan [2] Division of Colon and Rectum, Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: S-W
authors.initials: SW
authors.lastname: Chang
authors.affiliation: 1] School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan [2] Division of Gastroenterology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: T-H
authors.initials: TH
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: H
authors.initials: H
authors.lastname: Lee
mesh_terms: D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D051419:Paxillin / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C000595707:BCL2 protein, human; C496061:PXN protein, human; D051419:Paxillin; D019253:Proto-Oncogene Proteins c-bcl-2; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D005472:Fluorouracil