Targeting inhibitors of the tumor suppressor PP2A for the treatment of pancreatic cancer.
Targeting inhibitors of the tumor suppressor PP2A for the treatment of pancreatic cancer.
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DOI：
10.1158/1541-7786.mcr-13-0542
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发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Sears RC
中科院分区：
文献类型：
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作者：
Farrell AS;Allen-Petersen B;Daniel CJ;Wang X;Wang Z;Rodriguez S;Impey S;Oddo J;Vitek MP;Lopez C;Christensen DJ;Sheppard B;Sears RC
胰腺癌是一种致命的疾病，通常在晚期被诊断出来，此时几乎没有有效的治疗方法。鉴于这种疾病的侵袭性临床过程和缺乏良好的治疗选择，开发用于治疗胰腺癌的新治疗剂是最重要的。几种被证明有助于胰腺癌进展的途径受到肿瘤抑制因子蛋白磷酸酶2A（PP 2A）的负调控。在此，PP 2A的内源性抑制剂SET（也称为I2 PP 2A）和PP 2A的癌症抑制剂（CIP 2A）显示在人胰腺癌中过表达，导致PP 2A活性降低，以及癌蛋白c-Myc（一种关键PP 2A靶标）的过表达和稳定。SET或CIP 2A的敲低增加PP 2A活性，增加c-Myc降解，并降低胰腺癌细胞系在体外和体内的致瘤潜力。此外，用新型SET抑制剂OP 449治疗可重现几种胰腺癌细胞系的表型并显著降低其增殖和致瘤潜力，同时伴随细胞生长和存活信号的减弱。此外，胰腺癌患者的原代细胞对OP 449治疗敏感，表明PP 2A调节途径与这种致命疾病高度相关。
Pancreatic cancer is a deadly disease that is usually diagnosed in the advanced stages when few effective therapies are available. Given the aggressive clinical course of this disease and lack of good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Several pathways shown to contribute to pancreatic cancer progression are negatively regulated by the tumor suppressor, protein phosphatase 2A (PP2A). Here, the endogenous inhibitors of PP2A, SET (also known as I2PP2A) and Cancerous Inhibitor of PP2A (CIP2A), were shown to be overexpressed in human pancreatic cancer, contributing to decreased PP2A activity, and overexpression and stabilization of the oncoprotein c-Myc, a key PP2A target. Knockdown of SET or CIP2A increases PP2A activity, increases c-Myc degradation, and decreases the tumorigenic potential of pancreatic cancer cell lines both in vitro and in vivo. Moreover, treatment with a novel SET inhibitor, OP449, pharmacologically recapitulates the phenotypes and significantly reduces proliferation and tumorigenic potential of several pancreatic cancer cell lines, with an accompanying attenuation of cell growth and survival signaling. Furthermore, primary cells from pancreatic cancer patients were sensitive to OP449 treatment, indicating that PP2A regulated pathways are highly relevant to this deadly disease.