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

Oncogene volume 23, pages 4847–4855 (2004)Cite this article

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 β-catenin increased in Cyr61 stably transfected H520 cells. Moreover, β-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 β-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 β-catenin. In this pathway, Cyr61 activated the β-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.

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Acknowledgements

This work was supported in part by the NIH Lung Spore grant CA90388 as well as support from the Parker Hughes Trust. HPK is the recipient of the Goodson Endowed Chair in Oncology Research and is a member of the Jonsson Cancer Center and the Molecular Biology Institute of UCLA.

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  1. Xiangjun Tong and James O'Kelly: Both these authors contributed equally to this work

Authors and Affiliations

  1. Divisions of Hematology/Oncology and Surgery, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, 90048, CA, USA

    Xiangjun Tong, James O'Kelly, Dong Xie, Akio Mori, Nathan Lemp, Robert McKenna, Carl W Miller & H Phillip Koeffler

  2. College of Life Sciences, Peking University, Beijing, 100871, China

    Xiangjun Tong

  3. Institute for Nutritional Sciences, SIBS, Chinese Academy of Sciences, Shanghai, China

    Dong Xie

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Tong, X., O'Kelly, J., Xie, D. et al. Cyr61 suppresses the growth of non-small-cell lung cancer cells via the β-catenin–c-myc–p53 pathway. Oncogene 23, 4847–4855 (2004). https://doi.org/10.1038/sj.onc.1207628

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