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J. Biol. Chem., Vol. 279, Issue 23, 24015-24023, June 4, 2004

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

Ming-Tsan Lin, Cheng-Chi Chang¶, Szu-Ta Chen||, Huei-Ling Chang**, Jen-Liang Su¶, Yat-Pang Chau, and Min-Liang Kuo¶

From the Department of Surgery and the ^||Department of Pediatrics, National Taiwan University Hospital, Taipei 100, Taiwan, ^**Cooperative Laboratory at VGH-Taipei, Cancer Research Division, National Health Research Institutes, Taipei 112, Taiwan, ^¶Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan, and Institute of Anatomy, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan

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 -lapachone. Most interesting, gel shift and reporter assays showed that the Cyr61-overexpressing cells had significantly increased NF-B activity compared with neo control cells. Blockage of NF-B activity in Cyr61-expressing cells by transfecting with a dominant negative (DN)-IB or with an NF-B decoy rendered them more susceptible to anti-cancer drugs-induced apoptosis. In addition, several NF-B-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-IB to block NF-B activity also effectively reduced the elevated XIAP level. Function-neutralizing antibodies to _v3 and _v5 could inhibit Cyr61-mediated NF-B 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-B/XIAP signaling pathway.

Received for publication, March 1, 2004

^* This work was supported by Grants NSC92-2320-B-002-067, NSC92-2320-B0002-120, and NSC92-2323-B-002-010 from the National Science Council, Taiwan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this article.

To whom correspondence should be addressed: Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, Number 1, Section 1, Jen-Ai Rd., Taipei, Taiwan. Tel.: 886-2-3970800 (ext. 8607); Fax: 886-2-23410217; E-mail: toxkml{at}ha.mc.ntu.edu.tw.

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