SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases

Muthusamy Thangaraju, Elangovan Gopal, Pamela Moore Martin, Sudha Ananth, Sylvia B Smith, Puttur D Prasad, Esta Sterneck, Vadivel Ganapathy

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)11560-11564
Number of pages5
JournalCancer Research
Volume66
Issue number24
DOIs
StatePublished - Dec 15 2006

Fingerprint

Histone Deacetylases
Pyruvic Acid
Apoptosis
Lactic Acid
Neoplasms
MCF-7 Cells
Up-Regulation
Down-Regulation
TNF-Related Apoptosis-Inducing Ligand Receptors
Breast Neoplasms
Butyrates
Propionates
Glycolysis
DNA Methylation
Tumor Cell Line
L-Lactate Dehydrogenase
Isoenzymes
Breast
Cell Death
Complementary DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases. / Thangaraju, Muthusamy; Gopal, Elangovan; Martin, Pamela Moore; Ananth, Sudha; Smith, Sylvia B; Prasad, Puttur D; Sterneck, Esta; Ganapathy, Vadivel.

In: Cancer Research, Vol. 66, No. 24, 15.12.2006, p. 11560-11564.

Research output: Contribution to journalArticle

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