Perrotti Danilo, Neviani Paolo
Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Cancer Metastasis Rev. 2008 Jun;27(2):159-68. doi: 10.1007/s10555-008-9119-x.
Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases and is involved in the regulation of cell homeostasis through the negative regulation of signaling pathways initiated by protein kinases. As several cancers are characterized by the aberrant activity of oncogenic kinases, it was not surprising that a phosphatase like PP2A has progressively been considered as a potential tumor suppressor. Indeed, multiple solid tumors (e.g. melanomas, colorectal carcinomas, lung and breast cancers) present with genetic and/or functional inactivation of different PP2A subunits and, therefore, loss of PP2A phosphatase activity towards certain substrates. Likewise, impaired PP2A phosphatase activity has been linked to B-cell chronic lymphocytic leukemia, Philadelphia-chromosome positive acute lymphoblastic leukemia and blast crisis chronic myelogenous leukemia. Remarkably, drugs such as forskolin, 1,9-dideoxy-forskolin and FTY720 which lead to PP2A activation effectively antagonize leukemogenesis in both in vitro and in vivo models of these cancers. Thus, PP2A is now in the spotlight as a highly promising drugable target for the development of a new series of anticancer agents potentially capable of overcoming drug-resistance induced in patients by continuous exposure to kinase inhibitor monotherapy. Herein, we review current knowledge of PP2A biology and function with particular emphasis on its tumor suppressor activity and possible therapeutic implications in cancer.
蛋白磷酸酶2A（PP2A）是主要的细胞丝氨酸 - 苏氨酸磷酸酶之一，通过对蛋白激酶启动的信号通路进行负调控，参与细胞内稳态的调节。由于多种癌症的特征是致癌激酶的异常活性，像PP2A这样的磷酸酶逐渐被认为是一种潜在的肿瘤抑制因子也就不足为奇了。事实上，多种实体瘤（如黑色素瘤、结直肠癌、肺癌和乳腺癌）存在不同PP2A亚基的基因和/或功能失活，因此丧失了PP2A对某些底物的磷酸酶活性。同样，PP2A磷酸酶活性受损与B细胞慢性淋巴细胞白血病、费城染色体阳性急性淋巴细胞白血病和慢性粒细胞白血病急变期有关。值得注意的是，如福斯可林、1,9 - 二脱氧福斯可林和FTY720等能导致PP2A激活的药物，在这些癌症的体外和体内模型中均能有效拮抗白血病发生。因此，PP2A作为一个极具潜力的可成药靶点，有望开发出一系列新型抗癌药物，这些药物可能克服因持续接受激酶抑制剂单药治疗而导致患者产生的耐药性，目前正备受关注。在此，我们综述了关于PP2A生物学和功能的现有知识，特别强调其肿瘤抑制活性以及在癌症中的潜在治疗意义。
