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

Daniele Gilkes, Lisha Xiang, Sun Joo Lee, Pallavi Chaturvedi, Maimon E. Hubbi, Denis Wirtz, Gregg L Semenza

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number3
DOIs
StatePublished - Jan 21 2014

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Focal Adhesion Protein-Tyrosine Kinases
Breast Neoplasms
Myosin Light Chains
Myosin-Light-Chain Kinase
rho-Associated Kinases
Focal Adhesions
Critical Pathways
Myosins
GTP-Binding Proteins
Actins
Phosphorylation
Phenotype
Mutation
Hypoxia
Neoplasms

Keywords

  • Cytoskeletal reprogramming
  • Metastasis
  • Migration
  • Oxygen
  • Tumor microenvironment

ASJC Scopus subject areas

  • General

Cite this

Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells. / Gilkes, Daniele; Xiang, Lisha; Lee, Sun Joo; Chaturvedi, Pallavi; Hubbi, Maimon E.; Wirtz, Denis; Semenza, Gregg L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 3, 21.01.2014.

Research output: Contribution to journalArticle

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AU - Hubbi, Maimon E.

AU - Wirtz, Denis

AU - Semenza, Gregg L

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AB - 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.

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