title: 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.
abstract: 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-G(1) fraction of the cell cycle and in phosphatidyl serine externalization. A proapoptotic molecule, Bad, was phosphorylated constitutively at Ser(112) but not Ser(136) 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.
authors.affiliation: Division of Molecular Bioregulation and Center for Target Drug Development, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934 , Japan.
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Li
authors.forename: Boryana K
authors.initials: BK
authors.lastname: Popivanova
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nagai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishikura
authors.forename: Chifumi
authors.initials: C
authors.lastname: Fujii
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
mesh_terms: D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051025:bcl-Associated Death Protein / Q000378:metabolism*
chemical_list: C494819:BAD protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051025:bcl-Associated Death Protein; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases