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HIN-1, an Inhibitor of Cell Growth, Invasion, and AKT Activation

Departments of ¹ Medical Oncology and ² Biostatistics, Dana-Farber Cancer Institute; ³ Harvard Medical School, Boston, Massachusetts; ⁴ Department of Surgery, Nagoya City University Medical School, Nagoya, Japan; and Departments of ⁵ Medicine and ⁶ Epidemiology, Columbia University, New York, New York

Requests for reprints: Kornelia Polyak, Dana-Farber Cancer Institute, 44 Binney Street, D740C, Boston, MA 02115. Phone: 617-632-2106; Fax: 617-632-4005; E-mail: Kornelia_Polyak{at}dfci.harvard.edu.

The HIN-1 gene encoding a small, secreted protein is silenced due to methylation in a substantial fraction of breast, prostate, lung, and pancreatic carcinomas, suggesting a potential tumor suppressor function. The receptor of HIN-1 is unknown, but ligand-binding studies indicate the presence of high-affinity cell surface HIN-1 binding on epithelial cells. Here, we report that HIN-1 is a potent inhibitor of anchorage-dependent and anchorage-independent cell growth, cell migration, and invasion. Expression of HIN-1 in synchronized cells inhibits cell cycle reentry and the phosphorylation of the retinoblastoma protein (Rb), whereas in exponentially growing cells, HIN-1 induces apoptosis without apparent cell cycle arrest and effect on Rb phosphorylation. Investigation of multiple signaling pathways revealed that mitogen-induced phosphorylation and activation of AKT are inhibited in HIN-1–expressing cells. In addition, expression of constitutively activate AKT abrogates HIN-1–mediated growth arrest. Taken together, these studies provide further evidence that HIN-1 possesses tumor suppressor functions, and that these activities may be mediated through the AKT signaling pathway.

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