Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, U.K.
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, U.K.
Biochem J. 2019 Aug 15;476(15):2255-2269. doi: 10.1042/BCJ20190121.
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an adverse biomarker across many malignancies. Using K562 cells engineered to have high or low CIP2A expression, we show that high CIP2A levels significantly bias cellular energy production towards oxidative phosphorylation (OXPHOS) rather than glycolysis. Mass spectrometric analysis of CIP2A interactors and isobaric tagging for relative and absolute protein quantitation (ITRAQ) experiments identified many associated proteins, several of which co-vary with CIP2A level. Many of these CIP2A associating and co-varying proteins are involved in energy metabolism including OXPHOS, or in 5' AMP-activated protein kinase (AMPK) signalling, and manipulating AMPK activity mimics the effects of low/high CIP2A on OXPHOS. These effects are dependent on the availability of nutrients, driven by metabolic changes caused by CIP2A. CIP2A level did not affect starvation-induced AMPK phosphorylation of Unc-51 autophagy activating kinase 1 (ULK-1) at Ser555, but autophagy activity correlated with an increase in AMPK activity, to suggest that some AMPK processes are uncoupled by CIP2A, likely via its inhibition of protein phosphatase 2A (PP2A). The data demonstrate that AMPK mediates this novel CIP2A effect on energy generation in malignant cells.
癌蛋白磷酸酶 2A 的抑制剂（CIP2A）是许多恶性肿瘤的不良生物标志物。使用 K562 细胞工程设计高或低 CIP2A 表达，我们表明高 CIP2A 水平显著偏向细胞能量产生朝向氧化磷酸化（OXPHOS）而不是糖酵解。CIP2A 相互作用体的质谱分析和相对和绝对蛋白质定量的同重同位素标记（ITRAQ）实验鉴定了许多相关蛋白，其中几个与 CIP2A 水平共变。这些 CIP2A 相关和共变的蛋白许多涉及能量代谢，包括 OXPHOS，或涉及 5' AMP 激活的蛋白激酶（AMPK）信号转导，并且操纵 AMPK 活性模拟低/高 CIP2A 对 OXPHOS 的影响。这些影响依赖于营养物质的可用性，由 CIP2A 引起的代谢变化驱动。CIP2A 水平不影响饥饿诱导的自噬激活激酶 1（ULK-1）在 Ser555 处的 AMPK 磷酸化，但自噬活性与 AMPK 活性增加相关，表明某些 AMPK 过程被 CIP2A 解耦，可能通过其对蛋白磷酸酶 2A（PP2A）的抑制。数据表明，AMPK 介导了 CIP2A 对恶性细胞能量产生的这种新作用。
