Cyr61 suppresses the growth of non-small-cell lung cancer cells via the beta-catenin-c-myc-p53 pathway.

Abstract

Cysteine-rich protein 61 (Cyr61) is a growth factor-inducible, immediate-early gene that has multifaceted activities in various cancers. In a previous study, we found that Cyr61 inhibited the growth of the H520 and H460 non-small-cell lung cancer (NSCLC) cell lines. In further studies, we now report that p53 plays a pivotal role in Cyr61-dependent cellular growth arrest. Blocking Cyr61 with a Cyr61 antibody resulted in the downregulation of expression of p53 and p21, as well as partially reversing the growth suppression of H520-Cyr61 cells. Proliferation of NSCLC cell lines (NCI-H157, H125, H1299), having a mutant p53, were not suppressed by Cyr61. Inhibition of wild-type p53, by either human papilloma virus type 16 E6 or a dominant-negative p53, resulted in the rescue of the growth suppression mediated by Cyr61 in the H520-Cyr61 cells. The enhanced levels of p21WAF1 and p130/RB2, in the Cyr61-expressing H520-Cyr61 cells, were also inhibited by blocking p53 showing that p21 and p130 were induced by p53 in these cells. In addition, levels of both c-myc and beta-catenin increased in Cyr61 stably transfected H520 cells. Moreover, beta-catenin was translocated into the nucleus in these cells. Inhibition of c-myc expression in the H520-Cyr61 cells with antisense c-myc resulted in their decreased levels of p53. Transfecting cells with a dominant-negative T-cell factor (TCF4), the specific inhibitor of the beta-catenin/TCF4 complex, downregulated the expression of c-myc. Taken together, the data suggest that Cyr61 suppressed the growth of NSCLC cells by triggering a signal transduction pathway through beta-catenin. In this pathway, Cyr61 activated the beta-catenin/TCF4 complex, which promoted the expression of c-myc and the latter induced expression of p53, and p53 upregulated p21WAF1 and p130/RB2, resulting in growth arrest.

• Authors: Xiangjun Tong, James O'Kelly, Dong Xie, Akio Mori, Nathan Lemp, Robert McKenna, Carl W Miller, H Phillip Koeffler
• Journal: Oncogene (Oncogene) Vol. 23 Issue 28 Pg. 4847-55 (Jun 17 2004) ISSN: 0950-9232 [Print] England
• PMID: 15077166 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2004 Nature Publishing Group

Chemical References

• CCN1 protein, human
• CTNNB1 protein, human
• Cysteine-Rich Protein 61
• Cytoskeletal Proteins
• Immediate-Early Proteins
• Intercellular Signaling Peptides and Proteins
• Proto-Oncogene Proteins c-myc
• Recombinant Proteins
• Trans-Activators
• Tumor Suppressor Protein p53
• beta Catenin

Topics

• Carcinoma, Non-Small-Cell Lung (pathology)
• Cell Division (physiology)
• Cell Line, Tumor
• Cysteine-Rich Protein 61
• Cytoskeletal Proteins (physiology)
• Humans
• Immediate-Early Proteins (antagonists & inhibitors, immunology, physiology)
• Intercellular Signaling Peptides and Proteins (immunology, physiology)
• Lung Neoplasms (pathology)
• Models, Biological
• Proto-Oncogene Proteins c-myc (physiology)
• Recombinant Proteins (metabolism)
• Trans-Activators (physiology)
• Transfection
• Tumor Suppressor Protein p53 (physiology)
• beta Catenin