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Matrix Protein CCN1 Is Critical for Prostate Carcinoma Cell Proliferation and TRAIL-Induced Apoptosis
Open accessPublished version of a preprint
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays an important role in immune surveillance and preferentially induces apoptosis in cancer cells over normal cells, suggesting its potential in cancer therapy. However, the molecular basis for its selective killing of cancer cells is not well understood. Recent studies have identified the CCN family of integrin-binding matricellular proteins as important regulators of cell behavior, including cell adhesion, proliferation, migration, differentiation, and survival. We show here that CCN1 (CYR61) supports the adhesion of prostatic carcinoma cells as an adhesion substrate through integrins and heparan sulfate proteoglycans. Knockdown of CCN1 expression in PC-3 and DU-145 androgen-independent prostate cancer cells strongly inhibited their proliferation without causing apoptosis, indicating that CCN1 promotes their growth. However, CCN1 also significantly enhances TRAIL-induced apoptosis through interaction with integrins αvβ3 and α6β4 and the cell-surface heparan sulfate proteoglycan syndecan-4, acting through a protein kinase Cα-dependent mechanism without requiring de novo protein synthesis. Knockdown of CCN1 expression in PC-3, DU-145, and LNCaP cells severely blunted their sensitivity to TRAIL, an effect that was reversed by exogenously added CCN1 protein. These findings reveal a functional dichotomy for CCN1 in prostate carcinoma cells, because it contributes to both cell proliferation and TRAIL-induced cell death and suggest that CCN1 expression status may be an important parameter in assessing the efficacy of TRAIL-dependent cancer therapy. (Mol Cancer Res 2009;7(7):1045–55)
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“This activity may contribute to its ability to promote growth factor-induced poliferation in PC3 prostate cancer cells [76,77] and ovarian carcinoma cells [78], and IL-17-stimulated proliferation in synoviocytes [79].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [77]
In the citing paper
“In addition, CCN1 also strongly enhances the apoptotic activity of other apoptotic members of the TNF family, including FasL and TRAIL [77,106].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [77]
In the citing paper
“As described above, CCN1 profoundly alters the activities of inflammatory cytokines such as TNF-α and FasL in vitro and in vivo, and significantly enhances the cytotoxicity of TRAIL [77,111].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [77]
In the citing paper
“As described above, CCN1 profoundly alters the activities of inflammatory cytokines such as TNF-α and FasL in vitro and in vivo, and significantly enhances the cytotoxicity of TRAIL [77,111].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [77]
In the citing paper
“For example, whereas CCN1 can promote the proliferation of prostate cancer cells, CCN1 can also exacerbate apoptosis of these cells in the presence of the immune surveillance molecule TRAIL [74,76,77].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [77]
In the citing paper
“For example, whereas CCN1 can promote the proliferation of prostate cancer cells, CCN1 can also exacerbate apoptosis of these cells in the presence of the immune surveillance molecule TRAIL [74,76,77].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [77]
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References 50 · Cited by 66
Metadata
- Authors
- Franzen, C. A., Chen, C.-C., Todorović, V., Juric, V., Monzon, R. I., & Lau, L. F.
- Affiliations
- University of Illinois Chicago (US)
- Corresponding author
- Lau, Lester F.
- Venue
- Molecular Cancer Research
- Published
- 2009-07-15
- Volume
- 7
- Issue
- 7
- Pages
- 1045-1055
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- PMC
- PMC2712585
- OpenAlex
- W2164414468
- Cited by
- 66
- References
- 50
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 6 · 2015: 6 · 2014: 4 · 2013: 5 · 2012: 6
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA046565, CA-46565)
- National Institute of General Medical Sciences (R01GM078492, GM78492)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Bone and Dental Protein Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- CYR61, prostate cancer, TRAIL-induced apoptosis, cell proliferation, integrins, heparan sulfate proteoglycans, syndecan-4, integrin αvβ3, alpha6beta4 integrin, calpain, matricellular proteins, TRAIL sensitivity
- MeSH terms
- Cell Adhesion, Humans, Male, Prostatic Neoplasms, Integrins, Apoptosis, Reactive Oxygen Species, Heparan Sulfate Proteoglycans, Cell Line, Tumor, Cell Growth Processes, Protein Kinase C-alpha, TNF-Related Apoptosis-Inducing Ligand, Cysteine-Rich Protein 61
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