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Pim-3, a Proto-Oncogene with Serine/Threonine Kinase Activity, Is Aberrantly Expressed in Human Pancreatic Cancer and Phosphorylates Bad to Block Bad-Mediated Apoptosis in Human Pancreatic Cancer Cell Lines

¹ Division of Molecular Bioregulation and ² Center for Target Drug Development, Cancer Research Institute, ³ Venture Business Laboratory, Kanazawa University, Kanazawa, Japan and ⁴ Department of Molecular Pathology, Chiba University, Graduate School of Medicine, Chiba, Japan

Requests for reprints: Naofumi Mukaida, Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan. Phone: 81-76-265-2767; Fax: 81-76-234-4520; E-mail: naofumim{at}kenroku.kanazawa-u.ac.jp.

Pancreatic cancer still remains a serious health problem with <5% 5-year survival rate for all stages. To develop an effective treatment, it is necessary to identify a target molecule that is crucially involved in pancreatic tumor growth. We previously observed that Pim-3, a member of the proto-oncogene Pim family that expresses serine/threonine kinase activity, was aberrantly expressed in human and mouse hepatomas but not in normal liver. Here, we show that Pim-3 is also expressed in malignant lesions of the pancreas but not in normal pancreatic tissue. Moreover, Pim-3 mRNA and protein were constitutively expressed in all human pancreatic cancer cell lines that we examined and colocalized with the proapoptotic protein Bad. The ablation of endogenous Pim-3 by small hairpin RNA transfection promoted apoptosis, as evidenced by increases in a proportion of cells in the sub-G₁ fraction of the cell cycle and in phosphatidyl serine externalization. A proapoptotic molecule, Bad, was phosphorylated constitutively at Ser¹¹² but not Ser¹³⁶ in human pancreatic cancer cell lines and this phosphorylation is presumed to represent its inactive form. Phosphorylation of Bad and the expression of an antiapoptotic molecule, Bcl-X_L, were reduced by the ablation of endogenous Pim-3. Thus, we provide the first evidence that Pim-3 can inactivate Bad and maintain the expression of Bcl-X_L and thus prevent apoptosis of human pancreatic cancer cells. This may contribute to the net increase in tumor volume or tumor growth in pancreatic cancer. (Cancer Res 2006; 66(13): 6741-7)

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