Cyr61 suppresses the growth of non-small-cell lung cancer cells via the beta-catenin-c-myc-p53 pathway.
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.
Tong
Xiangjun
X
Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA.
O'Kelly
James
J
Xie
Dong
D
Mori
Akio
A
Lemp
Nathan
N
McKenna
Robert
R
Miller
Carl W
CW
Koeffler
H Phillip
HP
D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D055515:Cysteine-Rich Protein 61; D003598:Cytoskeletal Proteins / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000502:physiology*; D008175:Lung Neoplasms / Q000473:pathology*; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D051176:beta Catenin
C501848:CCN1 protein, human; C495270:CTNNB1 protein, human; D055515:Cysteine-Rich Protein 61; D003598:Cytoskeletal Proteins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin