RhoC interacts with integrin α5β1 and enhances its trafficking in migrating pancreatic carcinoma cells

Human pancreatic ductal adenocarcinoma (PDAC) is characterized by early systemic dissemination. Although RhoC has been implicated in cancer cell migration, the relevant underlying molecular mechanisms remain unknown. RhoC has been implicated in the enhancement of cancer cell migration and invasion,...

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Published in:	PloS one Vol. 8; no. 12; p. e81575
Main Authors:	Li, Ningfeng Fiona, Gemenetzidis, Emilios, Marshall, Francis J, Davies, Derek, Yu, Yongwei, Frese, Kristopher, Froeling, Fieke E M, Woolf, Adam K, Feakins, Roger M, Naito, Yoshiki, Iacobuzio-Donahue, Christine, Tuveson, David A, Hart, Ian R, Kocher, Hemant M
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 03-12-2013 Public Library of Science (PLoS)
Subjects:	Adenocarcinoma Adhesion Amino acids Animals Autopsies Autopsy Bioindicators Biology Biomarkers C-Terminus Cancer Cell Adhesion Cell adhesion & migration Cell Differentiation Cell migration Cell Movement Cloning Enzyme Activation Fibronectin Homology Humans Integrin alpha5beta1 - metabolism Internalization Invasiveness Localization Masking Medical research Metastases Metastasis Mice Molecular modelling Neoplasm Invasiveness Neoplasm Metastasis Overexpression Pancreatic cancer Pancreatic carcinoma Pancreatic Neoplasms Pancreatic Neoplasms - pathology Pathology Plasmids Prostate cancer Protein Binding Protein Transport rho GTP-Binding Proteins - genetics rho GTP-Binding Proteins - metabolism RhoA protein rhoC GTP-Binding Protein Rodents Signal Transduction src-Family Kinases - metabolism Tumor cells United Kingdom > UK United States > US Maryland Baltimore Maryland
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Summary:	Human pancreatic ductal adenocarcinoma (PDAC) is characterized by early systemic dissemination. Although RhoC has been implicated in cancer cell migration, the relevant underlying molecular mechanisms remain unknown. RhoC has been implicated in the enhancement of cancer cell migration and invasion, with actions which are distinct from RhoA (84% homology), and are possibly attributed to the divergent C-terminus domain. Here, we confirm that RhoC significantly enhances the migratory and invasive properties of pancreatic carcinoma cells. In addition, we show that RhoC over-expression decreases cancer cell adhesion and, in turn, accelerates cellular body movement and focal adhesion turnover, especially, on fibronectin-coated surfaces. Whilst RhoC over-expression did not alter integrin expression patterns, we show that it enhanced integrin α5β1 internalization and re-cycling (trafficking), an effect that was dependent specifically on the C-terminus (180-193 amino acids) of RhoC protein. We also report that RhoC and integrin α5β1 co-localize within the peri-nuclear region of pancreatic tumor cells, and by masking the CAAX motif at the C-terminal of RhoC protein, we were able to abolish this interaction in vitro and in vivo. Co-localization of integrin α5β1 and RhoC was demonstrable in invading cancer cells in 3D-organotypic cultures, and further mimicked in vivo analyses of, spontaneous human, (two distinct sources: operated patients and rapid autopsy programme) and transgenic murine (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre), pancreatic cancers. In both cases, co-localization of integrin α5β1 and RhoC correlated with poor differentiation status and metastatic potential. We propose that RhoC facilitates tumor cell invasion and promotes subsequent metastasis, in part, by enhancing integrin α5β1 trafficking. Thus, RhoC may serve as a biomarker and a therapeutic target.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: NFL EG FJM HMK. Performed the experiments: NFL EG FJM FEMF AKW HMK. Analyzed the data: NFL EG FJM DD YY IRH HMK. Contributed reagents/materials/analysis tools: KF DAT YN CI-D DD RMF HMK. Wrote the manuscript: NFL EG IRH HMK. Competing Interests: The funding from Hutchinson Whampoa Limited does not alter our adherence to all the PLOS ONE policies on sharing data and materials.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0081575