Therapeutic relevance of the protein phosphatase 2A in cancer.
Therapeutic relevance of the protein phosphatase 2A in cancer.
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DOI：
10.18632/oncotarget.11399
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发表时间：
2016-09-20
期刊：
影响因子：
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通讯作者：
Vizeacoumar FJ
中科院分区：
文献类型：
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作者：
Cunningham CE;Li S;Vizeacoumar FS;Bhanumathy KK;Lee JS;Parameswaran S;Furber L;Abuhussein O;Paul JM;McDonald M;Templeton SD;Shukla H;El Zawily AM;Boyd F;Alli N;Mousseau DD;Geyer R;Bonham K;Anderson DH;Yan J;Yu-Lee LY;Weaver BA;Uppalapati M;Ruppin E;Sablina A;Freywald A;Vizeacoumar FJ
染色体不稳定性（CIN）被认为是异质肿瘤群体的统一特征，驱动肿瘤内异质性。polo样激酶1 （PLK1）是一种丝氨酸-苏氨酸激酶，在多种肿瘤类型中经常过表达，是CIN的关键调节因子之一，被认为是潜在的治疗靶点。然而，由于其他马球样家族成员的抑制导致脱靶效应，靶向PLK1仍然是一个挑战。在这里，我们使用合成剂量致死（SDL），其中PLK1的过表达只有在存在另一种通常非致死的突变或缺失时才致命。我们发现，抑制PP2A并不是直接抑制PLK1，而是对PLK1过表达的乳腺、胰腺、卵巢、胶质母细胞瘤和前列腺癌细胞造成选择性致死。由于PP2A被广泛认为是一种肿瘤抑制因子，我们利用来自癌症患者的基因表达数据集从功能上剖析其治疗相关性。我们确定了两种主要的PP2A亚基，它们彼此负相关。有趣的是，大多数有丝分裂调节因子，包括PLK1，仅与一类PP2A亚基（PPP2R1A, PPP2R2D, PPP2R3B， PPP2R5B和PPP2R5D）表现出SDL相互作用。验证研究和其他基于功能细胞的实验表明，抑制PPP2R5D会影响plk1过表达细胞中磷酸化rb的水平以及姐妹染色单体的内聚。最后，临床数据分析显示，有丝分裂调节因子高表达和PP2A I类亚单位低表达的患者生存率提高。总的来说，这些观察结果表明PP2A的环境依赖性作用值得进一步探索其治疗益处。
Chromosomal Instability (CIN) is regarded as a unifying feature of heterogeneous tumor populations, driving intratumoral heterogeneity. Polo-Like Kinase 1 (PLK1), a serine-threonine kinase that is often overexpressed across multiple tumor types, is one of the key regulators of CIN and is considered as a potential therapeutic target. However, targeting PLK1 has remained a challenge due to the off-target effects caused by the inhibition of other members of the polo-like family. Here we use synthetic dosage lethality (SDL), where the overexpression of PLK1 is lethal only when another, normally non-lethal, mutation or deletion is present. Rather than directly inhibiting PLK1, we found that inhibition of PP2A causes selective lethality to PLK1-overexpressing breast, pancreatic, ovarian, glioblastoma, and prostate cancer cells. As PP2A is widely regarded as a tumor suppressor, we resorted to gene expression datasets from cancer patients to functionally dissect its therapeutic relevance. We identified two major classes of PP2A subunits that negatively correlated with each other. Interestingly, most mitotic regulators, including PLK1, exhibited SDL interactions with only one class of PP2A subunits (PPP2R1A, PPP2R2D, PPP2R3B, PPP2R5B and PPP2R5D). Validation studies and other functional cell-based assays showed that inhibition of PPP2R5D affects both levels of phospho-Rb as well as sister chromatid cohesion in PLK1-overexpressing cells. Finally, analysis of clinical data revealed that patients with high expression of mitotic regulators and low expression of Class I subunits of PP2A improved survival. Overall, these observations point to a context-dependent role of PP2A that warrants further exploration for therapeutic benefits.