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Cited by 163TGF-β signaling in diseasesProtease and Inhibitor MechanismsMechanisms of cancer metastasis

The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.

Cystatin C Antagonizes Transforming Growth Factor β Signaling in Normal and Cancer Cells

Sokol, Jonathan P., Schiemann, William P.·2004·Molecular Cancer Research
DOI 10.1158/1541-7786.183.2.3
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Abstract

Cystatin C (CystC) is a secreted cysteine protease inhibitor that regulates bone resorption, neutrophil chemotaxis, and tissue inflammation, as well as resistance to bacterial and viral infections. CystC is ubiquitously expressed and present in most bodily fluids where it inhibits the activities of cathepsins, a family of cysteine proteases that can promote cancer cell invasion and metastasis. Transforming growth factor β (TGF-β) is a multifunctional cytokine endowed with both tumor-suppressing and tumor-promoting activities. We show herein that TGF-β treatment up-regulated CystC transcript and protein in murine 3T3-L1 fibroblasts. Moreover, CystC mRNA expression was down-regulated in ∼50% of human malignancies, particularly cancers of the stomach, uterus, colon, and kidney. Overexpression of CystC in human HT1080 fibrosarcoma cells antagonized their invasion through synthetic basement membranes in part via a cathepsin-dependent pathway. Independent of effects on cathepsin activity, CystC also reduced HT1080 cell gene expression stimulated by TGF-β. Invasion of 3T3-L1 cells occurred through both cathepsin- and TGF-β-dependent pathways. Both pathways were blocked by CystC, but only the TGF-β-dependent pathway was blocked by a CystC mutant (i.e., Δ14CystC) that is impaired in its ability to inhibit cathepsin activity. Moreover, CystC and Δ14CystC both inhibited 3T3-L1 cell gene expression stimulated by TGF-β. We further show that CystC antagonized TGF-β binding to its cell surface receptors, doing so by interacting physically with the TGF-β type II receptor and antagonizing its binding of TGF-β. Collectively, our findings have identified CystC as a novel TGF-β receptor antagonist, as well as a novel CystC-mediated feedback loop that inhibits TGF-β signaling.

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Crossref · 10.1158/1541-7786.183.2.3

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Citations

Cites

Research works printed but not linked: 4

  1. Kos J, Krasovec M, Cimerman N, Nielsen HJ, Christensen IJ, Brunner N. Cysteine proteinase inhibitors stefin A, stefin B, and cystatin C in sera from patients with colorectal cancer: relation to prognosis. Clin Cancer Res, 2000;6:505–11.
  2. Szpaderska AM, Frankfater A. An intracellular form of cathepsin B contributes to invasiveness in cancer. Cancer Res, 2001;61:3493–500.
  3. Rowland-Goldsmith MA, Maruyama H, Kusama T, Ralli S, Korc M. Soluble type II transforming growth factor-β (TGF-β) receptor inhibits TGF-β signaling in COLO-357 pancreatic cancer cells in vitro and attenuates tumor formation. Clin Cancer Res, 2001;7:2931–40.
  4. Won J, Kim H, Park EJ, Hong Y, Kim SJ, Yun Y. Tumorigenicity of mouse thymoma is suppressed by soluble type II transforming growth factor β receptor therapy. Cancer Res, 1999;59:1273–7.

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Metadata

Authors
Sokol, J. P., & Schiemann, W. P.
Affiliations
National Jewish Health (US)
ORCID
Schiemann, William P.
Venue
Molecular Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2004-03-01
Volume
2
Issue
3
Pages
183-195
ISSN
  • 1541-7786 (ISSN-L)
  • 1557-3125
DOI
10.1158/1541-7786.183.2.3
OpenAlex
W4292964442
Cited by
121
References
60
Citations by year
2026: 1 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 1 · 2018: 10 · 2017: 10 · 2016: 8 · 2015: 3 · 2014: 4 · 2013: 5 · 2012: 2
FWCI
3.08
Type
journal article
Language
en
Open access
closed
Locations
Molecular Cancer Research (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
cystatin C, TGF-beta, TGF-beta signaling, cathepsins, cysteine protease inhibitors, TGFBR2, cell invasion, fibroblasts, fibrosarcoma, cancer gene expression, tumor suppression

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