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Cited by 196Cell death mechanisms and regulationConnective Tissue Growth Factor ResearchSignaling Pathways in Disease

Cyr61 Expression Confers Resistance to Apoptosis in Breast Cancer MCF-7 Cells by a Mechanism of NF-κB-dependent XIAP Up-Regulation

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Lin, Ming-Tsan, Chang, Cheng-Chi, Chen, Szu-Ta, Chang, Huei-Ling, Su, Jen-Liang, Chau, Yat-Pang, Kuo, Min-Liang·2004·Journal of Biological Chemistry
DOI 10.1074/jbc.m402305200
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Abstract

The aggressiveness of a tumor is partly attributed to its resistance to chemotherapeutic agent-induced apoptosis. Cysteine-rich 61 (Cyr61), from the CCN gene family, is a secreted and matrix-associated protein, which is involved in many cellular activities such as growth and differentiation. Here we established a cell model system to examine whether stable expression of Cyr61 in MCF-7 cells can confer resistance to apoptosis and identify possible participating mechanisms. We showed that stable cell lines overexpressing Cyr61 had acquired a remarkable resistance to apoptosis induced by paclitaxel, adriamycin, and β-lapachone. Most interesting, gel shift and reporter assays showed that the Cyr61-overexpressing cells had significantly increased NF-κB activity compared with neo control cells. Blockage of NF-κB activity in Cyr61-expressing cells by transfecting with a dominant negative (DN)-IκB or with an NF-κB decoy rendered them more susceptible to anti-cancer drugs-induced apoptosis. In addition, several NF-κB-regulated anti-apoptotic genes were examined, and we found that only XIAP showed a significant 3–4-fold increase in mRNA and protein in Cyr61-overexpressing cells but not in neo control cells. Treatment with inhibitor of apoptosis protein (XIAP)-specific antisense, but not sense, oligonucleotides abolished the apoptosis resistance of the Cyr61-overexpressing cells. At the same time, transfection of these stable cells with DN-IκB to block NF-κB activity also effectively reduced the elevated XIAP level. Function-neutralizing antibodies to αvβ3 and αvβ5 could inhibit Cyr61-mediated NF-κB activation as well as XIAP expression. Taken together, our data suggested that Cyr61 plays an important role in resistance to chemotherapeutic agent-induced apoptosis in human breast cancer MCF-7 cells by a mechanism involving the activation of the integrins/NF-κB/XIAP signaling pathway. The aggressiveness of a tumor is partly attributed to its resistance to chemotherapeutic agent-induced apoptosis. Cysteine-rich 61 (Cyr61), from the CCN gene family, is a secreted and matrix-associated protein, which is involved in many cellular activities such as growth and differentiation. Here we established a cell model system to examine whether stable expression of Cyr61 in MCF-7 cells can confer resistance to apoptosis and identify possible participating mechanisms. We showed that stable cell lines overexpressing Cyr61 had acquired a remarkable resistance to apoptosis induced by paclitaxel, adriamycin, and β-lapachone. Most interesting, gel shift and reporter assays showed that the Cyr61-overexpressing cells had significantly increased NF-κB activity compared with neo control cells. Blockage of NF-κB activity in Cyr61-expressing cells by transfecting with a dominant negative (DN)-IκB or with an NF-κB decoy rendered them more susceptible to anti-cancer drugs-induced apoptosis. In addition, several NF-κB-regulated anti-apoptotic genes were examined, and we found that only XIAP showed a significant 3–4-fold increase in mRNA and protein in Cyr61-overexpressing cells but not in neo control cells. Treatment with inhibitor of apoptosis protein (XIAP)-specific antisense, but not sense, oligonucleotides abolished the apoptosis resistance of the Cyr61-overexpressing cells. At the same time, transfection of these stable cells with DN-IκB to block NF-κB activity also effectively reduced the elevated XIAP level. Function-neutralizing antibodies to αvβ3 and αvβ5 could inhibit Cyr61-mediated NF-κB activation as well as XIAP expression. Taken together, our data suggested that Cyr61 plays an important role in resistance to chemotherapeutic agent-induced apoptosis in human breast cancer MCF-7 cells by a mechanism involving the activation of the integrins/NF-κB/XIAP signaling pathway.

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  • CCN1 promotes endothelial cell survival through integrin αvβ3 and inhibits apoptosis by activating Akt in pulmonary epithelial cells or upregulating XIAP in MCF7 breast cancer cells.

    “CCN1 promotes the survival of endothelial cells through integrin αvβ3 [72], and inhibits apoptosis by activation of Akt in pulmonary epithelial cells [80] or upregulation of XIAP in MCF7 breast cancer cells [81].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [81]

  • Although CCN1 promotes cell survival in endothelial cells and some cancer cells, it represents the first example of an ECM molecule that can induce apoptosis through cell adhesion.

    “Although CCN1 promotes cell survival in endothelial cells and some cancer cells [72,81], it represents the first example of an ECM molecule that can induce apoptosis through the process cell adhesion [61].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [81]

  • Anti-apoptotic functions of CCN1 in breast cancer cells are mediated through integrin αvβ3.

    “The anti-apoptotic functions of CCN1 in breast cancer cells are mediated through its receptor integrin αvβ3 [81,153], whose expression is also induced by CCN1 [154].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [81]

  • In MCF7 breast cancer cells, overexpression of CCN1 confers significant resistance to apoptosis, in part through upregulation of XIAP.

    “In MCF7 breast cancer cells, which are dependent on estrogen for growth, overexpression of CCN1 renders these cells estrogen-independent and significantly resistant to apoptosis, in part through upregulation of the anti-apoptotic protein XIAP [81,152,153].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [81]

  • In MCF7 breast cancer cells, overexpression of CCN1 renders the cells estrogen-independent.

    “In MCF7 breast cancer cells, which are dependent on estrogen for growth, overexpression of CCN1 renders these cells estrogen-independent and significantly resistant to apoptosis, in part through upregulation of the anti-apoptotic protein XIAP [81,152,153].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [81]

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  1. Kim, H. S., Nagalla, S. R., Oh, Y., Wilson, E., Roberts, C. T., Jr., and Rosenfeld, R. G. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 12981-12986

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Authors
Lin, M.-T., Chang, C.-C., Chen, S.-T., Chang, H.-L., Su, J.-L., Chau, Y.-P., & Kuo, M.-L.
Affiliations
  • National Taiwan University Hospital (TW)
  • National Taiwan University (TW)
  • National Health Research Institutes (TW)
  • National Yang Ming University (TW)
Corresponding author
Kuo, Min-Liang
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2004-06
Volume
279
Issue
23
Pages
24015-24023
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m402305200
OpenAlex
W1983777512
Cited by
194
References
86
Citations by year
2026: 1 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 12 · 2021: 9 · 2020: 5 · 2019: 5 · 2018: 8 · 2017: 9 · 2016: 10 · 2015: 8 · 2014: 8 · 2013: 9 · 2012: 11
FWCI
4.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Science Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
CYR61, CCN family, apoptosis resistance, breast cancer, MCF-7 cells, NF-κB, XIAP, chemoresistance, integrins, integrin αvβ3, paclitaxel, doxorubicin, β-lapachone, antisense oligonucleotides, anti-apoptotic genes
MeSH terms
Antibiotics, Antineoplastic, Antineoplastic Agents, Phytogenic, Breast Neoplasms, Cell Division, Cell Nucleus, Cell Survival, DNA, Doxorubicin, Flow Cytometry, Genes, Dominant, Humans, Microscopy, Fluorescence, Models, Biological, Naphthoquinones, Promoter Regions, Genetic, Proteins, RNA, Messenger, Time Factors, Transfection, Blotting, Western, Signal Transduction, Up-Regulation, Integrins, NF-kappa B, Oligonucleotides, Antisense, Apoptosis, Paclitaxel, Immediate-Early Proteins, Genes, Reporter, Receptors, Vitronectin, Reverse Transcriptase Polymerase Chain Reaction, Active Transport, Cell Nucleus, Intercellular Signaling Peptides and Proteins, Integrin alphaVbeta3, Cell Line, Tumor, X-Linked Inhibitor of Apoptosis Protein, Cysteine-Rich Protein 61

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