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Cited by 92Caveolin-1 and cellular processesBladder and Urothelial Cancer TreatmentsMechanisms of cancer metastasis

Src and caveolin-1 reciprocally regulate metastasis via a common downstream signaling pathway in bladder cancer

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Thomas, Shibu, Overdevest, Jonathan B., Nitz, Matthew D., Williams, Paul D., Owens, Charles R., Sanchez-Carbayo, Marta, Frierson, Henry F., Schwartz, Martin A. +1 more·2011·Cancer Research
DOI 10.1158/0008-5472.can-10-0730PMC PMC4306590

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Abstract

In bladder cancer, increased caveolin-1 (Cav-1) expression and decreased Src expression and kinase activity correlate with tumor aggressiveness. Here, we investigate the clinical and functional significance, if any, of this reciprocal expression in bladder cancer metastasis. We evaluated the ability of tumor Cav-1 and Src RNA and protein expression to predict outcome following cystectomy in 257 patients enrolled in two independent clinical studies. In both, high Cav-1 and low Src levels were associated with metastasis development. We overexpressed or depleted Cav-1 and Src protein levels in UMUC-3 and RT4 human bladder cancer cells and evaluated the effect of this on actin stress fibers, migration using Transwells, and lung metastasis following tail vein inoculation. Cav-1 depletion or expression of active Src in metastatic UMUC-3 cells decreases actin stress fibers, cell migration, and metastasis, while Cav-1 overexpression or Src depletion increased the migration of nonmetastatic RT4 cells. Biochemical studies indicated that Cav-1 mediates these effects via its phosphorylated form (pY14), whereas Src effects are mediated through phosphorylation of p190RhoGAP and these pathways converge to reduce activity of RhoA, RhoC, and Rho effector ROCK1. Treatment with a ROCK inhibitor reduced UMUC-3 lung metastasis in vivo, phenocopying the effect of Cav-1 depletion or expression of active Src. Src suppresses whereas Cav-1 promotes metastasis of bladder cancer through a pharmacologically tractable common downstream signaling pathway. Clinical evaluation of personalized therapy to suppress metastasis development based on Cav-1 and Src profiles seems warranted. Cancer Res; 71(3); 832–41. ©2010 AACR.

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  • p190-RhoGAP inactivates RhoA and not Cdc42 and Rac1, but does not differentiate among RhoA, RhoB, and RhoC.

    “For example, p190-RhoGAP inactivates RhoA and not Cdc42 and Rac1 [27], but it does not differentiate among RhoA, RhoB, and RhoC [28].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [28]

    Citation [28] is attached to the claim that p190-RhoGAP does not differentiate among RhoA, RhoB, and RhoC. The Results section reports that p190RhoGAP knockdown increased activation of both RhoA and RhoC in RT4 cells, but it does not assess RhoB. The separate claim about Cdc42 and Rac1 is attached to [27], not this source. No page number is available in our copy. (LLM, conf=0.84)

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Cited by

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Authors
Thomas, S., Overdevest, J. B., Nitz, M. D., Williams, P. D., Owens, C. R., Sanchez-Carbayo, M., Frierson, H. F., Schwartz, M. A., & Theodorescu, D.
Affiliations
  • Spanish National Cancer Research Centre (ES)
  • Authors' Affiliations: Departments of 1Molecular Physiology and Biological Physics, 2Microbiology, and 3Pathology, University of Virginia, Charlottesville, Virginia; 4Tumor Markers Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, Melchor Fernandez Almagro 3, Madrid, Spain; and 5University of Colorado Comprehensive Cancer Center, Aurora, Colorado
Corresponding author
Theodorescu, Dan
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2011-02-01
Volume
71
Issue
3
Pages
832-841
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-10-0730
PMC
PMC4306590
OpenAlex
W2155418737
Cited by
92
References
1
Citations by year
2026: 4 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 6 · 2019: 3 · 2018: 1 · 2017: 6 · 2016: 9 · 2015: 9 · 2014: 10 · 2013: 14 · 2012: 7
FWCI
3.27
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (R01CA075115)
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK069264)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
  • Health Sciences › Medicine › Surgery › Bladder and Urothelial Cancer Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
bladder cancer, caveolin-1, Src kinase, metastasis, lung metastasis, stress fibers, cell migration, RhoA, RhoC, ROCK1, p190RhoGAP, caveolin-1 phosphorylation, prognostic factors
MeSH terms
Actins, Animals, Urinary Bladder Neoplasms, Cell Movement, Disease Models, Animal, Humans, Lung Neoplasms, Biomarkers, Tumor, Signal Transduction, src-Family Kinases, rho GTP-Binding Proteins, Stress Fibers, Cell Line, Tumor, Caveolin 1, Mice, rho-Associated Kinases

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