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Galanin and galanin receptor type 1 suppress proliferation in squamous carcinoma cells: activation of the extracellular signal regulated kinase pathway and induction of cyclin-dependent kinase inhibitors

Oncogene volume 26, pages 5762–5771 (2007)Cite this article

Abstract

Galanin receptor 1 (GALR1) maps to a common region of 18q loss in head and neck squamous cell carcinomas and is frequently inactivated by methylation. To investigate effects of GALR1 and its signaling pathways, we stably expressed hemaglutinin-tagged GALR1 in a human oral carcinoma cell line (UM-SCC-1-GALR1) that expresses no endogenous GALR1. In transfected cells, galanin induced activation of the extracellular-regulated protein kinase-1/2 (ERK1/2) and suppressed proliferation. Galanin stimulation mediated decreased expression of cyclin D1 and increased expression of the cyclin-dependent kinase inhibitors (CKI), p27Kip1 and p57Kip2. Pretreatment with the ERK1/2-specific inhibitor U0126 prevented these galanin-induced effects. Phosphatidylinositol 3-kinase (PI3K) pathway activation did not differ in UM-SCC-1-GALR1 and UM-SCC-1-mock cells after galanin treatment. Pertussis toxin and LY294002 inhibition demonstrated that galanin and GALR1 induce ERK1/2 activation via Gαi, not the PI3K pathway-linked to the Gβγ subunit. Galanin and GALR1 also inhibit colony formation and tumor growth in vivo. Our results implicate GALR1, a Gi protein-coupled receptor, as a tumor suppressor gene that inhibits cell proliferation via ERK1/2 activation.

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Acknowledgements

This work was supported by National Institutes of Health grants R01 DE12477, University of Michigan Head and Neck SPORE Grant P50 CA97248, University of Michigan's Cancer Center Support Grant P30 CA46592, a Research Resources Core grant NIH NIDCD P30 DC05188, and a Grant-in-Aid for Scientific Research (No. 452662) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Authors and Affiliations

  1. Department of Otolaryngology/Head and Neck Surgery, Laboratory of Head and Neck Cancer Biology, The University of Michigan, Ann Arbor, MI, USA

    T Kanazawa, P Kommareddi, T Nair, K Misawa, Y Misawa, Y Ueda & T E Carey

  2. Department of Otolaryngology, Head and Neck Surgery, University of Ryukyus, Okinawa, Japan

    T Kanazawa & T Tono

  3. Departments of Internal Medicine and Cell and Developmental Biology, The University of Michigan, Ann Arbor, MI, USA

    T Iwashita

  4. Department of Otolaryngology, Hamamatsu University School of Medicine, Hamamatsu, Japan

    K Misawa, Y Misawa & Y Ueda

  5. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA

    T E Carey

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  1. T Kanazawa
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Correspondence to T E Carey.

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Kanazawa, T., Iwashita, T., Kommareddi, P. et al. Galanin and galanin receptor type 1 suppress proliferation in squamous carcinoma cells: activation of the extracellular signal regulated kinase pathway and induction of cyclin-dependent kinase inhibitors. Oncogene 26, 5762–5771 (2007). https://doi.org/10.1038/sj.onc.1210384

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