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Frequent requirement of hedgehog signaling in non-small cell lung carcinoma

Oncogene volume 26, pages 1046–1055 (2007)Cite this article

Abstract

Although it had previously been suggested that the hedgehog (HH) pathway might be activated in some lung tumors, the dependence of non-small cell lung carcinomas (NSCLC) for HH activity had not been comprehensively studied. During a screen of a panel of 60 human tumor cell lines with an HH antagonist, we observed that the proliferation of a subset of NSCLC cell lines was inhibited. These NSCLC cell lines express HH, as well as key HH target genes, consistent with them being activated through an autocrine mechanism. Interestingly, we also identified a number of NSCLC cell lines that express high levels of the downstream transcription factor GLI1 and harbor enhanced levels of HH activity, but appear insensitive to known HH antagonists. We hypothesized that the high levels of GLI1 in these cells would function downstream of the HH antagonist target, allowing them to bypass the antagonist-mediated block in proliferation. Consistent with this hypothesis, when the levels of GLI1 are knocked down in such cells, they become sensitive to these inhibitors. We go on to show that a large percentage of primary NSCLC samples express GLI1, consistent with constitutive activation of the HH pathway in these samples. Taken together, these results establish the involvement of the HH signaling pathway in a subset of NSCLCs.

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Acknowledgements

This work was supported by National Institutes of Health Grants RO1 GM64011 (DJR) and P30 CA023108 (DJR), the Hitchcock Foundation (ZY) and National Institute of Health Grant T32 CA09658-14 (SKO). This work was also supported by National Institute of Health and National Cancer Institute Grants RO1-CA87546 (ED), RO1-CA111422 (ED), RO1-CA62275 (ED), the Oracle Giving Fund (ED) and the Samuel Waxman Cancer Research Foundation (ED). WJP was supported by the CHEST Foundation and the National Research Service Award from the National Institutes of Health T32-CA009658 and the American Society of Clinical Oncology (ASCO) Young Investigator Award. We gratefully acknowledge the DTP at the NCI for performing the initial SANT1 screen of the NCI-60 panel. We are also grateful to members of the Robbins and Dmitrovsky laboratories for helpful discussions during the course of this work.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA

    Z Yuan, J A Goetz, S Singh, S K Ogden, E Dmitrovsky & D J Robbins

  2. Department of Medicine, Dartmouth Medical School, Hanover, NH, USA

    W J Petty & E Dmitrovsky

  3. Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    W J Petty

  4. Department of Pathology, Dartmouth Medical School, Hanover, NH, USA

    C C Black & V A Memoli

  5. Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH, USA

    C C Black, V A Memoli, E Dmitrovsky & D J Robbins

  6. Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

    C C Black, V A Memoli & E Dmitrovsky

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  1. Z Yuan
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Correspondence to D J Robbins.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Yuan, Z., Goetz, J., Singh, S. et al. Frequent requirement of hedgehog signaling in non-small cell lung carcinoma. Oncogene 26, 1046–1055 (2007). https://doi.org/10.1038/sj.onc.1209860

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