https://scholars.lib.ntu.edu.tw/handle/123456789/191985
標題: | Cyr61 Expression Confers Resistance to Apoptosis in Breast Cancer Mcf-7 Cells by a Mechanism of Nf-Kappa B-Dependent Xiap up-Regulation | 作者: | LIN, MING-TSAN | 公開日期: | 2004 | 卷: | v.279 | 期: | n.23 | 起(迄)頁: | 24015-24023 | 來源出版物: | JOURNAL OF BIOLOGICAL CHEMISTRY | 摘要: | 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 beta-lapachone. Most interesting, gel shift and reporter assays showed that the Cyr61- overexpressing cells had significantly increased NF- kappaB activity compared with neo control cells. Blockage of NF-kappaB activity in Cyr61- expressing cells by transfecting with a dominant negative (DN)-IkappaB or with an NF-kappaB decoy rendered them more susceptible to anti- cancer drugs-induced apoptosis. In addition, several NF- kappaB-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-IkappaB to block NF-kappaB activity also effectively reduced the elevated XIAP level. Function-neutralizing antibodies to alpha(v)beta(3) and alpha(v)beta(5) could inhibit Cyr61-mediated NF-kappaB 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-kappaB/XIAP signaling pathway. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/91649 |
顯示於: | 醫學系 |
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