title: Cisplatin at sub-toxic levels mediates integrin switch in lung cancer cells.
abstract: BACKGROUND
  Resistance to chemotherapeutic agents, as well as enhanced metastasis, have been frequently reported in lung cancer.
  
  
  METHODS
  Cytotoxicity and proliferative effects of cisplatin on H460 lung cancer cells were evaluated by the MTT assay. Migration capacity was evaluated by the wound healing assay. The number of filopodia per cell were detected by rhodamine-phalloidin staining assay. The changes of protein levels of integrins, and migration-related proteins in response to cisplatin at sub-toxic concentrations were determined by western blotting.
  
  
  RESULTS
  Herein we demonstrate for the first time that exposure to low concentrations of cisplatin results in increase of cell motility with the alteration of integrin expression. Cisplatin-treated cells exhibited a significant increase in the number of filopodia per cell in correlation with enhanced migration. Migration regulatory proteins, namely activated forms of focal-adhesion kinase (FAK) and ATP-dependent tyrosine kinase (AKT), were found to significantly be up-regulated in cisplatin-treated cells in comparison to those of the non-treated control. Active Rho A-GTP and Rac-GTP were found to be increased in accordance with activation of FAK/AKT signals. Furthermore, we found that such migration enhancement may be in part due to the integrin switch mediated by cisplatin treatment. Cisplatin induced a dramatic alteration in the integrin expression pattern by up-regulating integrin α4, αv, β1, and β5 which were previously reported to increase cell motility, while it had no effect on integrin α5, and β3.
  
  
  CONCLUSIONS
  As the integrin switch is a hallmark of highly aggressive cancer, these findings may provide insights for better understanding of cancer cell adaptation after exposure to cisplatin.
authors.affiliation: Cell-based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Arnatchai
authors.initials: A
authors.lastname: Maiuthed
authors.affiliation: Cell-based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand pithi_chan@yahoo.com.
authors.forename: Pithi
authors.initials: P
authors.lastname: Chanvorachote
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000096:biosynthesis; D006801:Humans; D039001:Integrin alpha Chains / Q000096:biosynthesis*; D039641:Integrin beta Chains / Q000096:biosynthesis*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D011554:Pseudopodia / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D020744:rac GTP-Binding Proteins / Q000096:biosynthesis; D054460:rho-Associated Kinases / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D020744:rac GTP-Binding Proteins; D002945:Cisplatin
keywords: Integrin; cisplatin; lung cancer; metastasis; migration