SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases
SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases
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DOI：
10.1158/0008-5472.can-06-1950
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发表时间：
2006-12-15
期刊：
影响因子：
11.2
通讯作者：
Ganapathy, Vadivel
中科院分区：
文献类型：
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作者：
Thangaraju, Muthusamy;Gopal, Elangovan;Ganapathy, Vadivel
肿瘤细胞上调糖酵解，但将丙酮酸转化为乳酸而不是将其氧化。在这里，我们证明丙酮酸（而不是乳酸）是组蛋白脱乙酰酶 (HDAC) 的抑制剂和肿瘤细胞凋亡的诱导剂，而 SLC5A8（一种 Na+/单羧酸盐协同转运蛋白）是该过程所必需的。我们发现SLC5A8在未转化的乳腺上皮细胞系中表达，但在肿瘤细胞系中被DNA甲基化沉默。该基因的下调在原发性乳腺肿瘤中也很明显。当 MCF7 乳腺肿瘤细胞转染 SLC5A8 cDNA 时，细胞会经历丙酮酸依赖性细胞凋亡。丁酸盐和丙酸盐还会诱导 SLC5A8 表达细胞凋亡，而乳酸则不会。这些单羧酸盐在表达 SLC5A8 的 MCF7 细胞中引起细胞凋亡的不同能力与其抑制 HDAC 的能力相关。 MCF7 细胞中 SLC5A8/丙酮酸诱导的细胞凋亡与 p53、Bax、肿瘤坏死因子相关凋亡诱导配体 (TRAIL)、TRAIL 受体 (TRAILR) I 和 TRAILR2 的上调以及 Bcl2 和 survivin 的下调有关。乳酸脱氢酶同工酶在非转化细胞和肿瘤细胞中差异表达，使得后者将丙酮酸转化为乳酸。与未转化细胞相比，肿瘤细胞中 SLC5A8 的沉默以及丙酮酸转化为乳酸与这些细胞中 HDAC 活性的增加相关。因此，我们的研究将丙酮酸确定为 HDAC 抑制剂，并表明 Na+ 偶联的丙酮酸转运是 SLC5A8 肿瘤抑制作用的基础。我们建议肿瘤细胞沉默 SLC5A8 并将丙酮酸转化为乳酸作为补充机制以避免丙酮酸诱导的细胞死亡。
Tumor cells up-regulate glycolysis but convert pyruvate into lactate instead of oxidizing it. Here, we show that pyruvate, but not lactate, is an inhibitor of histone deacetylases (HDAC) and an inducer of apoptosis in tumor cells and that SLC5A8, a Na+/monocarboxylate cotransporter, is obligatory for this process. We found that SLC5A8 is expressed in nontransformed breast epithelial cell lines but silenced by DNA methylation in tumor cell lines. The down-regulation of the gene is also evident in primary breast tumors. When MCF7 breast tumor cells are transfected with SLC5A8 cDNA, the cells undergo pyruvate-dependent apoptosis. Butyrate and propionate also induce apoptosis in SLC5A8-expressing cells, whereas lactate does not. The differential ability of these monocarboxylates to cause apoptosis in SLC5A8-expressing MCF7 cells correlates with their ability to inhibit HDACs. Apoptosis induced by SLC5A8/pyruvate in MCF7 cells is associated with up-regulation of p53, Bax, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL receptor (TRAILR) I, and TRAILR2 and down-regulation of Bcl2 and survivin. Lactate dehydrogenase isozymes are differentially expressed in nontransformed cells and tumor cells such that the latter convert pyruvate into lactate. Silencing of SLC5A8 coupled with conversion of pyruvate into lactate in tumor cells correlates with increased HDAC activity in these cells compared with nontransformed cells. Our studies thus identify pyruvate as a HDAC inhibitor and indicate that the Na+-coupled pyruvate transport underlies the tumor-suppressive role of SLC5A8. We propose that tumor cells silence SLC5A8 and convert pyruvate into lactate as complementary mechanisms to avoid pyruvate-induced cell death.