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Induction of tumor suppression and glandular differentiation of A549 lung carcinoma cells by dominant-negative IGF-I receptor

Oncogene volume 18, pages 6071–6077 (1999)Cite this article

Abstract

Overexpression or activation of insulin-like growth factor I receptor (IGF-IR) has been observed in many human cancers including breast, lung, colon and gastric carcinomas. We demonstrate that inhibition of the endogenous insulin-like growth factor I receptor by stable expression of a dominant-negative IGF-IR represses the transforming activity in vitro and tumorigenicity of human lung carcinoma cells A549 in vivo. The suppression of tumorigenicity in nude mice is correlated with the induction of glandular differentiation. In addition, functional inhibition of the endogenous receptor dramatically increases the sensitivity of A549 cells to a variety of apoptotic signals including UV irradiation and proteasome inhibitors. These effects are due to the formation of a stable heterocomplex of the dominant-negative receptor with the endogenous wild type receptor which reduces the kinase activity of the latter by twofold. Thus, inhibition of the IGF-IR signaling pathway not only suppresses tumorigenicity but also enhances sensitivity to apoptosis-inducing agents. Antagonizing IGF-IR signaling by promoting tumor differentiation and enhancing sensitivity to apoptotic death are potential cancer therapeutic approaches.

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Acknowledgements

We thank Drs Lu-Hai Wang and Hua Cheng for anti-IGF-IR antibody, IGF-IR cDNA and pBEFneo vector, respectively. This work was supported by Lola and Allen Goldring Clinical Scholars Fund (to Y Jiang), National Institutes of Health Grants MO1-RR00096, RO1-HL59832 and 62055 (to WN Rom), and RO1-ES09161 and American Lung Association Research Grant Award (to K-M Tchou-Wong).

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Authors and Affiliations

  1. Department of Medicine, Division of Pulmonary and Critical Care Medicine, New York University Medical Center, 550 First Avenue, MSB 147, New York, 10016, NY, USA

    Yixing Jiang, William N Rom, Ting-An Yie, Chuan Xiang Chi & Kam-Meng Tchou-Wong

  2. Department of Environmental Medicine, Division of Pulmonary and Critical Care Medicine, New York University Medical Center, 550 First Avenue, MSB 147, New York, 10016, NY, USA

    William N Rom

  3. Department of Pathology, Division of Pulmonary and Critical Care Medicine, 550 First Avenue, MSB 147, New York, 10016, NY, USA

    William N Rom

  4. Department of Microbiology, Division of Pulmonary and Critical Care Medicine, New York University Medical Center, 550 First Avenue, MSB 147, New York, 10016, NY, USA

    Kam-Meng Tchou-Wong

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  1. Yixing Jiang
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Jiang, Y., Rom, W., Yie, TA. et al. Induction of tumor suppression and glandular differentiation of A549 lung carcinoma cells by dominant-negative IGF-I receptor. Oncogene 18, 6071–6077 (1999). https://doi.org/10.1038/sj.onc.1202984

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