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J. Biol. Chem., Vol. 280, Issue 24, 22564-22571, June 17, 2005

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Galanin Receptor 1 Has Anti-proliferative Effects in Oral Squamous Cell Carcinoma^*

Bradley S. Henson, Richard R. Neubig¶, Ilwhan Jang||, Tetsuya Ogawa||, Zhaocheng Zhang, Thomas E. Carey||, and Nisha J. D'Silva**

From the Departments of Oral Medicine, Pathology, and Oncology, University of Michigan School of Dentistry, and ^¶Internal Medicine, ^||Otolaryngology, Laboratory of Head and Neck Cancer Biology, The University of Michigan Medical School and the Comprehensive Cancer Center, Ann Arbor, Michigan, 48109-0506

In the United States, oral cancer accounts for more deaths annually than cervical cancer, leukemias, or Hodgkin's lymphoma. Studies have shown that aberrations of chromosome 18q develop with tumor progression and are associated with significantly decreased survival in head and neck cancer patients. The G-protein-coupled receptor, galanin receptor 1 (GALR1), maps to this region of chromosome 18q. Although the role of GALR1 has been well characterized in neuronal cells, little is known regarding this receptor in non-neuronal cells. In this study, the expression, mitogenic function, and signaling mechanism of GALR1 are investigated in normal and malignant oral epithelial cells. mRNA expression was determined via reverse transcriptase-PCR. Protein quantification was done via immunoblot analysis and enzyme-linked immunosorbent assay. For functional and signaling studies, an inhibitory antibody was generated to the N-terminal ligand binding domain of GALR1. GALR1 protein and mRNA expression and GAL secretion were detected at variable levels in immortalized human oral keratinocytes and human oropharyngeal squamous cell carcinoma cell lines. Upon competitive inhibition of GALR1, proliferation was up-regulated in immortalized and malignant keratinocytes. Furthermore, studies with the inhibitory antibody and U0126, the MAPK inhibitor, show that GALR1 inhibits proliferation in immortalized and malignant keratinocytes by inactivating the MAPK pathway. GALR1s inhibitory effects on proliferation in epithelial cells raises the possibility that inactivation or disregulation of this receptor can lead to uncontrolled proliferation and neoplastic transformation.

Received for publication, December 27, 2004 , and in revised form, February 22, 2005.

^* This work was supported by NIDCR DE00452-01 and NCI SPORE Grant P50 CA97248. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported in part by a Mentored Clinical Scientist Development Award (K08 DE014620-01A1) and Institutional Research Training Grant T32 DE07057, both from NIDCR, as well as a Dean's Scholarship from the University of Michigan School of Dentistry.

^** To whom correspondence should be addressed: Dept. of Oral Medicine, Pathology, and Oncology, University of Michigan, School of Dentistry, 1011 N. University Ave., Rm. 5217 Ann Arbor, MI 48109-1078. Tel.: 734-764-1543; Fax: 734-764-2469; E-mail: njdsilva{at}umich.edu.

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