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PMID: 24324133 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 111 ·No. 3 ·2014-01-21 ·Pages E384-93

Gilkes DM, Xiang L, Lee SJ, Chaturvedi P, Hubbi ME, Wirtz D, Semenza GL

Abstract

Overexpression of Rho kinase 1 (ROCK1) and the G protein RhoA is implicated in breast cancer progression, but oncogenic mutations are rare, and the molecular mechanisms that underlie increased ROCK1 and RhoA expression have not been determined. RhoA-bound ROCK1 phosphorylates myosin light chain (MLC), which is required for actin-myosin contractility. RhoA also activates focal adhesion kinase (FAK) signaling. Together, these pathways are critical determinants of the motile and invasive phenotype of cancer cells. We report that hypoxia-inducible factors coordinately activate RhoA and ROCK1 expression and signaling in breast cancer cells, leading to cell and matrix contraction, focal adhesion formation, and motility through phosphorylation of MLC and FAK. Thus, intratumoral hypoxia acts as an oncogenic stimulus by triggering hypoxia-inducible factor → RhoA → ROCK1 → MLC → FAK signaling in breast cancer cells.

Keywords
cytoskeletal reprogramming metastasis migration oxygen tumor microenvironment
MeSH Terms
Animals Breast Neoplasms/metabolism Cell Hypoxia Cell Line, Tumor Cell Movement Cell Survival Collagen/chemistry Cytoskeleton/metabolism Female Gene Expression Regulation, Neoplastic HEK293 Cells Humans Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Microscopy, Confocal Mutation Neoplasm Metastasis Oligonucleotide Array Sequence Analysis Oxygen/metabolism Phosphorylation Rats Signal Transduction Tumor Microenvironment rho-Associated Kinases/metabolism rhoA GTP-Binding Protein/metabolism
Chemicals
HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit Collagen ROCK1 protein, human rho-Associated Kinases rhoA GTP-Binding Protein Oxygen
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Gilkes Daniele M
Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and Departments of Pediatrics, Oncology, Medicine, Radiation Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Xiang Lisha
Lee Sun Joo
Chaturvedi Pallavi
Hubbi Maimon E
Wirtz Denis
Semenza Gregg L
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1321510111
Published
2014-01-21
Epub
2013-00-09
Pages
E384-93
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3903228
Subset
IM
Grants
NCI NIH HHS · R01 CA174388 · United States
NCI NIH HHS · U54 CA143868 · United States
NCI NIH HHS · U54-CA143868 · United States
Corrections
CommentIn
PMID: 24398519
External Links
PubMed source DOI: 10.1073/pnas.1321510111 PMC Full Text View journal details
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