The plasma membrane transporter SLC5A8 suppresses tumour progression through depletion of survivin without involving its transport function.
The plasma membrane transporter SLC5A8 suppresses tumour progression through depletion of survivin without involving its transport function.
复制标题
DOI：
10.1042/bj20121248
复制
发表时间：
2013-02-15
期刊：
影响因子：
--
通讯作者：
Ganapathy V
中科院分区：
文献类型：
--
作者：
Coothankandaswamy V;Elangovan S;Singh N;Prasad PD;Thangaraju M;Ganapathy V
SLC5A8是一种钠偶联的单羧酸盐转运蛋白。它的底物包括HDAC抑制剂丁酸盐、丙酸和丙酮酸。在癌症中，SLC5A8的表达通过DNA甲基化而被沉默，而在癌细胞中异位表达的SLC5A8在其底物作为HDAC抑制剂的情况下诱导细胞凋亡。在这里，我们发现SLC5A8在癌细胞中的异位表达通过蛋白质-蛋白质相互作用将抗凋亡蛋白Survivin转移到质膜上，导致核Survivin的耗尽，并通过抑制转录来降低细胞Survivin的水平。这些SLC5A8诱导的Survivin的位置和水平的变化导致细胞周期停滞，破坏与有丝分裂有关的染色体乘客复合体，诱导细胞凋亡，并增强对化疗的敏感性。这些效应与SLC5A8的转运功能和细胞的组蛋白乙酰化状态无关；在存在SLC5A8底物丙酮酸和HDAC抑制剂的情况下，这些效应被放大。SLC5A8在乳腺癌细胞系MB231中的异位表达抑制了该细胞在体外形成克隆的能力和在体内形成小鼠异种移植瘤的能力。Survivin转录的抑制与HDAC的抑制无关，其基本机制与STAT3的磷酸化减少有关。观察到的作用是针对Survivin的，其他凋亡抑制蛋白的表达没有明显变化。这些研究揭示了一种新的、迄今未被认识的、不依赖于其转运功能的质膜转运体的肿瘤抑制作用机制。
SLC5A8 is a sodium-coupled transporter for monocarboxylates. Among its substrates are the HDAC inhibitors butyrate, propionate, and pyruvate. Expression of SLC5A8 is silenced in cancers via DNA methylation, and ectopic expression of SLC5A8 in cancer cells induces apoptosis in the presence of its substrates that are HDAC inhibitors. Here we show that ectopic expression of SLC5A8 in cancer cells translocates the anti-apoptotic protein survivin to plasma membrane through protein-protein interaction resulting in depletion of nuclear survivin and also decreases cellular levels of survivin through inhibition of transcription. These SLC5A8-induced changes in the location and levels of survivin result in cell cycle arrest, disruption of the chromosome passenger complex involved in mitosis, induction of apoptosis, and enhancement in chemosensitivity. These effects are seen independent of the transport function of SLC5A8 and histone acetylation status of the cell; in the presence of pyruvate, a SLC5A8 substrate and also an HDAC inhibitor, these effects are amplified. Ectopic expression of SLC5A8 in the breast cancer cell line MB231 inhibits the ability of the cell to form colonies in vitro and to form tumors in mouse xenografts in vivo. The suppression of survivin transcription occurs independent of HDAC inhibition, and the underlying mechanism is associated with decreased phosphorylation of STAT3. The observed effects are specific for survivin with no apparent changes in expression of other inhibitor-of-apoptosis proteins. These studies unravel a novel, hitherto unrecognized, mechanism for the tumor-suppressive role of a plasma membrane transporter independent of its transport function.