2007 Fiscal Year Final Research Report Summary
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
| Project/Area Number |
18591884
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Otorhinolaryngology
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| Research Institution | Jichi Medical University |
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Principal Investigator |
KANAZAWA Takeharu Jichi Medical University, School of medicine, Lecturer (20336374)
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| Co-Investigator(Kenkyū-buntansha) |
ICHIMURA Keiichi Jichi Medical University, School of medicine, Professor (00010471)
NISHINO Hiroshi Jichi Medical University, School of medicine, Associate Professor (50245057)
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| Project Period (FY) |
2006 – 2007
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| Keywords | GPCR / GALR1 / Tumor Suppressor Gene / Head and Neck Cancer |
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| Research Abstract |
Galanin receptor 1 (GALR1) maps to a common region of 18q loss on head and neck squamous cell carcinomas (HNSCC) and is frequently inactivated by methylation. To investigate effects of GALR1 and its signaling pathways, we stably expressed HA-tagged GALR1 in a human oral carcinoma cell line (UM-SCC-I-GALR1) that expresses no endogenous GALR1. In UM-SCC-1-GALR1 cells but not in mock transfected cells, galanin induced activation of the extracellular regulated protein kinase-1/2 (ERK1/2) and suppressed proliferation. Galanin stimulation also resulted in increased expression of the cyclin-dependent kinase inhibitors (CKI), p27Kip1 and p57Kip2 and decreased expression of cyclin Dl. Pretreatment of UM-SCC-I-GALR1 cells with the ERK1/2-specific inhibitor U0126 prevented these galanin-induced effects. There was no significant difference in phosphatidylinositol 3-kinase (PI3K) pathway activation between UM-SCC-1-GALR1 and UM-SCC-1-mock cells after galanin treatment-. Using the Giα protein specific inhibitor - pertussis toxin and the PI3K-specific inhibitor - LY294002, we show that galanin and GALR1 induce ERK1/2 activation via the Giα pathway, not the PI3K pathway-linked to the Gβγ subunit. Galanin and GALR1 also inhibit colony formation and xenografted tumor growth in vivo. Taken together, our results identify a novel mechanism whereby GALR1, a Giα protein-coupled receptor, inhibits cell proliferation by ERK1/2 activation.
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