Growth of the pancreatic cancer cell line PANC-1 is inhibited by protein phosphatase 2A inhibitors through overactivation of the c-Jun N-terminal kinase pathway
Growth of the pancreatic cancer cell line PANC-1 is inhibited by protein phosphatase 2A inhibitors through overactivation of the c-Jun N-terminal kinase pathway
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蛋白磷酸酶 2A 抑制剂通过过度激活 c-Jun N 末端激酶通路来抑制胰腺癌细胞系 PANC-1 的生长
DOI：
10.1016/j.ejca.2011.08.014
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发表时间：
2011-11-01
影响因子：
8.4
通讯作者：
Xu, Ze-Kuan
中科院分区：
文献类型：
--
作者：
Li, Wei;Chen, Zheng;Xu, Ze-Kuan
蛋白磷酸酶2A（PP 2A）是一种多聚体丝氨酸/苏氨酸磷酸酶，可使多种激酶脱磷酸化。它通常被认为是一种癌症抑制剂，因为它的抑制可以诱导主要加速生长的底物激酶的磷酸化和活化。我们以前报道过，黄芩苷，一种传统中药的活性成分，有效地和选择性地抑制PP 2A，但有效地抑制胰腺癌细胞的生长，通过激活c-Jun N-末端激酶（JNK）途径。这表明激活激酶通路也可能是癌症治疗的潜在策略。在这项研究中，我们证实，当受到生长因子刺激时，磷酸肌醇3-激酶（PI 3 K）/JNK/激活蛋白1（AP-1）途径的基础活性促进胰腺癌细胞生长。有趣的是，尽管用PP 2A抑制剂，藜芦定或冈田酸（OA）处理，放大了JNK的PI 3 K依赖性活化，但细胞生长受到抑制。因此，我们假设，一个特定水平的JNK通路的活性可能需要维持促有丝分裂功能，抑制和过度激活的JNK可以抑制细胞增殖。JNK依赖的细胞生长抑制不依赖于AP-1的激活，而依赖于Akt的抑制。虽然PP 2A抑制剂触发JNK的过度活化并抑制细胞生长，但过度活化的蛋白激酶C（PKC）改善了细胞存活。PP 2A抑制剂和PKC抑制剂的联合治疗产生了协同效应，这表明胰腺癌治疗的一种潜在的有希望的治疗方法。(C)2011爱思唯尔有限公司保留所有权利。
Protein phosphatase 2A (PP2A) is a multimeric serine/threonine phosphatase that can dephosphorylate multiple kinases. It is generally considered to be a cancer suppressor as its inhibition can induce phosphorylation and activation of substrate kinases that mainly accelerate growth. We previously reported that cantharidin, an active constituent of a traditional Chinese medicine, potently and selectively inhibited PP2A, yet efficiently repressed the growth of pancreatic cancer cells through activation of the c-Jun N-terminal kinase (JNK) pathway. This suggested that activation of kinase pathways might also be a potential strategy for cancer therapy. In this study, we have confirmed that the basal activity of the phospatidylinositol 3-kinase (PI3K)/JNK/activator protein 1 (AP-1) pathway promoted pancreatic cancer cell growth when stimulated by growth factors. Interestingly, although treatment with the PP2A inhibitors, cantharidin or okadaic acid (OA), amplified the PI3K-dependent activation of JNK, cell growth was repressed. We therefore hypothesised that a specific level of activity of the JNK pathway might be required to maintain the promitogenic function, as both repression and overactivation of JNK could inhibit cell proliferation. It was found that the JNK-dependent growth inhibition was independent of the activation of AP-1, but dependent on the repression of Akt. Although the PP2A inhibitors triggered overactivation of JNK and inhibited cell growth, excessively activated protein kinase C (PKC) improved cell survival. Combined treatment with a PP2A inhibitor and a PKC inhibitor produced a synergistic effect, which indicates a potentially promising therapeutic approach to pancreatic cancer treatment. (C) 2011 Elsevier Ltd. All rights reserved.