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Cyr61 Expression Confers Resistance To Apoptosis In Breast Cancer MCF-7 Cells By A Mechanism Of NF-κB-dependent XIAP Up-Regulation*

M. Lin, Cheng-Chi Chang, S. Chen, H. Chang, J. Su, Yat-Pang Chau, M. Kuo
Published 2004 · Medicine, Biology

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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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