15044484

pubmed:Citation

23

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.

http://linkedlifedata.com/resource/pubmed/journal/2985121R

http://linkedlifedata.com/resource/pubmed/chemical/Antibiotics, Antineoplastic, http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Phytogenic, http://linkedlifedata.com/resource/pubmed/chemical/CYR61 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Cysteine-Rich Protein 61, http://linkedlifedata.com/resource/pubmed/chemical/DNA, http://linkedlifedata.com/resource/pubmed/chemical/Doxorubicin, http://linkedlifedata.com/resource/pubmed/chemical/Immediate-Early Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Integrin alphaVbeta3, http://linkedlifedata.com/resource/pubmed/chemical/Integrins, http://linkedlifedata.com/resource/pubmed/chemical/Intercellular Signaling Peptides..., http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B, http://linkedlifedata.com/resource/pubmed/chemical/Naphthoquinones, http://linkedlifedata.com/resource/pubmed/chemical/Oligonucleotides, Antisense, http://linkedlifedata.com/resource/pubmed/chemical/Paclitaxel, http://linkedlifedata.com/resource/pubmed/chemical/Proteins, http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger, http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Vitronectin, http://linkedlifedata.com/resource/pubmed/chemical/X-Linked Inhibitor of Apoptosis..., http://linkedlifedata.com/resource/pubmed/chemical/XIAP protein, human, http://linkedlifedata.com/resource/pubmed/chemical/beta-lapachone, http://linkedlifedata.com/resource/pubmed/chemical/integrin alphaVbeta5

Jun

pubmed-author:ChangCheng-ChiCC, pubmed-author:ChangHuei-LingHL, pubmed-author:ChauYat-PangYP, pubmed-author:ChenSzu-TaST, pubmed-author:KuoMin-LiangML, pubmed-author:LinMing-TsanMT, pubmed-author:SuJen-LiangJL

4

NLM

24015-23

pubmed-meshheading:15044484-Active Transport, Cell Nucleus, pubmed-meshheading:15044484-Antibiotics, Antineoplastic, pubmed-meshheading:15044484-Antineoplastic Agents, Phytogenic, pubmed-meshheading:15044484-Apoptosis, pubmed-meshheading:15044484-Blotting, Western, pubmed-meshheading:15044484-Breast Neoplasms, pubmed-meshheading:15044484-Cell Division, pubmed-meshheading:15044484-Cell Line, Tumor, pubmed-meshheading:15044484-Cell Nucleus, pubmed-meshheading:15044484-Cell Survival, pubmed-meshheading:15044484-Cysteine-Rich Protein 61, pubmed-meshheading:15044484-DNA, pubmed-meshheading:15044484-Doxorubicin, pubmed-meshheading:15044484-Flow Cytometry, pubmed-meshheading:15044484-Genes, Dominant, pubmed-meshheading:15044484-Genes, Reporter, pubmed-meshheading:15044484-Humans, pubmed-meshheading:15044484-Immediate-Early Proteins, pubmed-meshheading:15044484-Integrin alphaVbeta3, pubmed-meshheading:15044484-Integrins, pubmed-meshheading:15044484-Intercellular Signaling Peptides and Proteins, pubmed-meshheading:15044484-Microscopy, Fluorescence, pubmed-meshheading:15044484-Models, Biological, pubmed-meshheading:15044484-NF-kappa B, pubmed-meshheading:15044484-Naphthoquinones, pubmed-meshheading:15044484-Oligonucleotides, Antisense, pubmed-meshheading:15044484-Paclitaxel, pubmed-meshheading:15044484-Promoter Regions, Genetic, pubmed-meshheading:15044484-Proteins, pubmed-meshheading:15044484-RNA, Messenger, pubmed-meshheading:15044484-Receptors, Vitronectin, pubmed-meshheading:15044484-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:15044484-Signal Transduction, pubmed-meshheading:15044484-Time Factors, pubmed-meshheading:15044484-Transfection, pubmed-meshheading:15044484-Up-Regulation, pubmed-meshheading:15044484-X-Linked Inhibitor of Apoptosis Protein

Cyr61 expression confers resistance to apoptosis in breast cancer MCF-7 cells by a mechanism of NF-kappaB-dependent XIAP up-regulation.

Journal Article, Research Support, Non-U.S. Gov't