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
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
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DOI：
10.1158/0008-5472.can-05-4272
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发表时间：
2006-07-01
期刊：
影响因子：
11.2
通讯作者：
Mukaida, Naofumi
中科院分区：
文献类型：
--
作者：
Li, Ying-Yi;Popivanova, Boryana K.;Mukaida, Naofumi
胰腺癌仍然是一个严重的健康问题，所有阶段的5年生存率<5%。为了开发一种有效的治疗方法，有必要确定一种与胰腺肿瘤生长密切相关的靶分子。我们以前观察到，Pim-3，原癌基因Pim家族的成员，表达丝氨酸/苏氨酸激酶活性，异常表达在人类和小鼠肝癌，但不是在正常肝脏。在这里，我们表明，Pim-3也表达在恶性病变的胰腺，但不是在正常的胰腺组织。此外，Pim-3的mRNA和蛋白质组成型表达在所有的人胰腺癌细胞系，我们检查和共定位与促凋亡蛋白坏。通过小发夹RNA转染的内源性Pim-3的消融促进了细胞凋亡，如通过在亚G、细胞周期分数和磷脂酰丝氨酸外化中的细胞比例的增加所证明的。在人胰腺癌细胞系中，促凋亡分子Bad在Ser（112）而不是Ser（136）处组成性磷酸化，并且这种磷酸化被认为代表其非活性形式。内源性Pim-3的消融降低了Bad的磷酸化和抗凋亡分子Bcl-X-L的表达。因此，我们首次证明Pim-3可以抑制Bad并维持Bcl-X-L的表达，从而阻止人胰腺癌细胞的凋亡。这可能有助于胰腺癌中肿瘤体积或肿瘤生长的净增加。
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, 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.