title: RCP induces Slug expression and cancer cell invasion by stabilizing β1 integrin.
abstract: Rab coupling protein (RCP)-induced tumor cell migration has been implicated in tumor pathophysiology and patient outcomes. In the present study, we demonstrate that RCP stabilizes β1 integrin leading to increased β1 integrin levels and activation of a signaling cascade culminating in Slug induction, epithelial-to-mesenchymal transition and increased invasion. Ectopic expression of RCP induced Slug expression. Silencing β1 integrin efficiently inhibited RCP-induced Slug expression and subsequent cancer cell invasion. Conversely, ectopic expression of β1 integrin was sufficient to induce Slug expression. Pharmacological inhibition of integrin linked kinase (ILK), EGFR and NF-κB, as well as transfection of a dominant-negative mutant of Ras (RasN17), significantly inhibited RCP-induced Slug expression and cancer cell invasion. Strikingly, ectopic expression of RCP was sufficient to enhance metastasis of ovarian cancer cells to the lung. Collectively, we demonstrate a mechanism by which RCP promotes cancer cell aggressiveness through sequential β1 integrin stabilization, activation of an ILK/EGFR/Ras/NF-κB signaling cascade and subsequent Slug expression.
authors.affiliation: Department of Pharmacology, College of Medicine, Konyang University, Daejeon, Korea.|Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Hwang
authors.affiliation: Department of Pharmacology, College of Medicine, Konyang University, Daejeon, Korea.
authors.forename: K H
authors.initials: KH
authors.lastname: Cho
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Jeong
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Park
authors.affiliation: Cancer Research Institute, Regional Cancer Center and Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: J M
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, College of Medicine, Konyang University, Daejeon, Korea.
authors.forename: S-L
authors.initials: SL
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, College of Medicine, Konyang University, Daejeon, Korea.
authors.forename: C G
authors.initials: CG
authors.lastname: Park
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Pharmacology, College of Medicine, Konyang University, Daejeon, Korea.
authors.forename: H Y
authors.initials: HY
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D019012:Integrin beta1; D008565:Membrane Proteins; C488966:RAB11FIP1 protein, human; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors