This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thangaraju, M. Articles by Ganapathy, V. Search for Related Content PubMed PubMed Citation Articles by Thangaraju, M. Articles by Ganapathy, V.

SLC5A8 Triggers Tumor Cell Apoptosis through Pyruvate-Dependent Inhibition of Histone Deacetylases

Departments of ¹ Biochemistry and Molecular Biology and ² Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia and ³ Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, Maryland

Requests for reprints: Vadivel Ganapathy, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912. Phone: 706-721-7652; Fax: 706-721-9947; E-mail: vganapat{at}mail.mcg.edu.

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) 1, 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. (Cancer Res 2006; 66(24): 11560-4)

This article has been cited by other articles:

				H. Frank, N. Groger, M. Diener, C. Becker, T. Braun, and T. Boettger Lactaturia and Loss of Sodium-dependent Lactate Uptake in the Colon of SLC5A8-deficient Mice J. Biol. Chem., September 5, 2008; 283(36): 24729 - 24737. [Abstract] [Full Text] [PDF]

				K. L. Bennett, M. Karpenko, M.-t. Lin, R. Claus, K. Arab, G. Dyckhoff, P. Plinkert, E. Herpel, D. Smiraglia, and C. Plass Frequently Methylated Tumor Suppressor Genes in Head and Neck Squamous Cell Carcinoma Cancer Res., June 15, 2008; 68(12): 4494 - 4499. [Abstract] [Full Text] [PDF]

				Y. Yamada, K. D. Davis, and C. R. Coffman Programmed cell death of primordial germ cells in Drosophila is regulated by p53 and the Outsiders monocarboxylate transporter Development, January 15, 2008; 135(2): 207 - 216. [Abstract] [Full Text] [PDF]