Involvement of PKC βII in anti-proliferating action of a new antitumor compound gnidimacrin
Involvement of PKC βII in anti-proliferating action of a new antitumor compound gnidimacrin
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DOI：
10.1002/ijc.11157
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发表时间：
2003-07-10
影响因子：
6.4
通讯作者：
Wakasugi, H
中科院分区：
文献类型：
--
作者：
Yoshida, M;Heike, Y;Wakasugi, H
daphnine -type二萜gnidimacrin （NSC 252940）对小鼠肿瘤和人肿瘤细胞系具有明显的抗肿瘤活性。该化合物结合并直接激活蛋白激酶C (PKC)，通过抑制人类K562白血病细胞的cdk2活性，将细胞周期阻滞在G期。在我们的研究中，我们检测了细胞PKC是否参与了尼克里马克林的抗增殖作用。将K562细胞暴露于高浓度的bryostatin 1 （0.11-3.3 muM）中24小时，PKC α和PKC β i的表达均下调，随后这些细胞根据PKC下调的程度对gniclimacrin产生抗性。此外，将PKC α和PKC β i基因转染到耐药的人肝癌HLE细胞中，发现PKC α阳性表达，PKC β i阴性表达。PKC β i基因转染后的细胞对gniclimacrin的敏感程度与PKC β i的表达程度有关。在连续4天的暴露中，最敏感的克隆显示0.001杯子/mL （1.2 nM）为IC50。而转染PKC α基因的细胞表现出PKC α表达的增加，并对gniclimacrin变得敏感，敏感性是PKC β i基因转染细胞的百分之一。这些结果表明PKC，特别是PKC β i，在尼克里马克林的抗肿瘤作用中是必需的。
Daphnane-type diterpene gnidimacrin (NSC 252940) shows significant antitumor activity against murine tumors and human tumor cell lines. This compound binds to and directly activates protein kinase C (PKC), arresting the cell cycle at the G, phase through inhibition of cdk2 activity in human K562 leukemia cells. In our study, we examined whether cellular PKC is involved in the antiproliferating effect of gniclimacrin. In a 24-hr exposure of K562 cells to high concentrations of bryostatin 1 (0.11-3.3 muM), both expression of PKC alpha and PKC betaII was downregulated, and thereafter these cells became resistant to gniclimacrin in response to the degree of PKC downregulation. In addition, PKC alpha and PKC betaII genes were transfected to gnidimacrin-resistant human hepatoma HLE cells that demonstrated positive expression of PKC a and negative expression of PKC betaII. PKC betaII gene-transfected cells became sensitive to gniclimacrin in relation to the degree of PKC betaII expression. The most sensitive clone to show 0.001 mug/mL (1.2 nM) as IC50 in a continuous 4-day exposure was obtained. While PKC alpha gene-transfected cells exhibited an increase in PKC alpha expression and became sensitive to gniclimacrin, sensitivity was one-hundredth of that in PKC betaII gene-transfected cells. These results suggest that PKC, in particular PKC betaII, is necessary in the antitumor effect of gniclimacrin.