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

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

doi:10.1158/0008-5472.can-06-1950

Cited by 121 publications

(138 citation statements)

References 20 publications

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“…Neoplastic cells accomplish the consumption of the surplus pyruvate generated by glycolysis, which is not fed into the TCA cycle, also by conversion into lactate by lactate dehydrogenase (LDH)-A (Shim et al, 1997) and by fueling it into lipid biosynthesis . Removal of this excess of pyruvate molecules is crucial to avoid pyruvate-induced apoptosis (Thangaraju et al, 2006). In addition, overexpression of the monocarboxylate transporter (MCT4) gene allows augmented extrusion of lactate along with protons to the extracellular milieu (Gallagher et al, 2007).…”

Section: The Metabolic Pattern Of Cancer Cellsmentioning

confidence: 99%

Metabolic reprogramming of the tumor

2012

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Cancer is classically considered as a genetic and, more recently, epigenetic multistep disease. Despite seminal studies in the 1920s by Warburg showing a characteristic metabolic pattern for tumors, cancer bioenergetics has often been relegated to the backwaters of cancer biology. This review aims to provide a historical account on cancer metabolism research, and to try to integrate and systematize the metabolic strategies in which cancer cells engage to overcome selective pressures during their inception and evolution. Implications of this renovated view on some common concepts and in therapeutics are also discussed.

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Section: The Metabolic Pattern Of Cancer Cellsmentioning

confidence: 99%

Metabolic reprogramming of the tumor

2012

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“…The Na ϩ -coupled monocarboxylate transporter SLC5A8 (human ortholog is in uppercase letters, and rodent ortholog is in lowercase letters) is necessary for the entry of butyrate into colon cells for subsequent inhibition of HDACs (14,15). Recently we have shown that propionate, another short-chain fatty acid produced in the colon by bacterial fermentation, is also an inhibitor of HDACs (16). SLC5A8 has been shown to function as a tumor suppressor in the colon (17) and other tissues (13,18,19); the ability of this transporter to mediate the Na ϩ -coupled entry of HDAC inhibitors (butyrate, propionate, and pyruvate) into cells underlies the tumor-suppressive function of this transporter (15,16).…”

Section: Dendritic Cells (Dcs)mentioning

confidence: 99%

“…Recently we have shown that propionate, another short-chain fatty acid produced in the colon by bacterial fermentation, is also an inhibitor of HDACs (16). SLC5A8 has been shown to function as a tumor suppressor in the colon (17) and other tissues (13,18,19); the ability of this transporter to mediate the Na ϩ -coupled entry of HDAC inhibitors (butyrate, propionate, and pyruvate) into cells underlies the tumor-suppressive function of this transporter (15,16). While SLC5A8 is necessary for the intracellular actions of butyrate, butyrate also elicits biologic effects on colon cells extracellularly by serving as an agonist for the cell surface G-protein-coupled receptor GPR109A, but without involving HDAC inhibition (20).…”

Section: Dendritic Cells (Dcs)mentioning

confidence: 99%

Blockade of Dendritic Cell Development by Bacterial Fermentation Products Butyrate and Propionate through a Transporter (Slc5a8)-dependent Inhibition of Histone Deacetylases

Singh

Thangaraju

Prasad

et al. 2010

Journal of Biological Chemistry

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246

165

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Mammalian colon harbors trillions of bacteria, yet there is no undue inflammatory response by the host against these bacteria under normal conditions. The bacterial fermentation products acetate, propionate, and butyrate are believed, at least in part, to be responsible for these immunosuppressive effects. Dendritic cells play an essential role in presentation of antigens to T lymphocytes and initiation of adaptive immune responses. Here we report that butyrate and propionate block the generation of dendritic cells from bone marrow stem cells, without affecting the generation of granulocytes. This effect is dependent on the Na ؉ -coupled monocarboxylate transporter Slc5a8, which transports butyrate and propionate into cells, and on the ability of these two bacterial metabolites to inhibit histone deacetylases. Acetate, which is also a substrate for Slc5a8 but not an inhibitor of histone deacetylases, does not affect dendritic cell development, indicating the essential role of histone deacetylase inhibition in the process. The blockade of dendritic cell development by butyrate and propionate is associated with decreased expression of the transcription factors PU.1 and RelB. Butyrate also elicits its biologic effects through its ability to activate the G-proteincoupled receptor Gpr109a, but this mechanism is not involved in butyrate-induced blockade of dendritic cell development. The participation of Slc5a8 and the non-involvement of Gpr109a in butyrate effects have been substantiated using bone marrow cells obtained from Slc5a8 ؊/؊ and Gpr109a ؊/؊ mice.These findings uncover an important mechanism underlying the anti-inflammatory functions of the bacterial fermentation products butyrate and propionate.Dendritic cells (DCs) 2 function as sentinels in peripheral tissues and lymphoid organs guarding against pathogens (1-3). Normally, microorganism-induced immunosuppression is associated with harmful effects in host. In certain cases however, the same process may have beneficial effects on host. Mammalian colon harbors trillions of bacteria without eliciting significant immune activation. There is a mutual beneficial relationship between the gut microbiota and the host (8, 9). The bacterial fermentation products acetate, propionate, and butyrate (collectively called short-chain fatty acids) are believed to be the mediators of the beneficial effects of gut bacteria on the host (10, 11). Among these short-chain fatty acids, butyrate has received the most attention for its biologic effects. The beneficial effects of butyrate on colon range from being a nutrient for colonocytes to being an anti-inflammatory and antitumor agent (12, 13). Although the anti-inflammatory function of butyrate is well known at the phenomenological level, the molecular mechanisms underlying the process are not fully understood.Butyrate is an inhibitor of histone deacetylases (HDACs) (12, 13). The Na ϩ -coupled monocarboxylate transporter SLC5A8 (human ortholog is in uppercase letters, and rodent ortholog is in lowercase letters) is necessary fo...

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“…We selected the breast cancer cell line MCF7 for this purpose. We have shown that breast cancer is also associated with the silencing of SLC5A8 and that MCF7 cell line, being a malignant cell, does not express the transporter (32). Therefore, a MCF7 cell line engineered to express SLC5A8 stably would be ideal for the screening.…”

Section: Slc5a8 As a Tumor Suppressor In Non-colonic Tissues: Mechanimentioning

confidence: 99%

Sodium-coupled Monocarboxylate Transporters in Normal Tissues and in Cancer

Ganapathy

Thangaraju

Gopal

et al. 2008

AAPS J

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202

187

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Abstract. SLC5A8 and SLC5A12 are sodium-coupled monocarboxylate transporters (SMCTs), the former being a high-affinity type and the latter a low-affinity type. Both transport a variety of monocarboxylates in a Na + -coupled manner. They are expressed in the gastrointestinal tract, kidney, thyroid, brain, and retina. SLC5A8 is localized to the apical membrane of epithelial cells lining the intestinal tract and proximal tubule. In the brain and retina, its expression is restricted to neurons and the retinal pigment epithelium. The physiologic functions of SLC5A8 include absorption of short-chain fatty acids in the colon and small intestine, reabsorption of lactate and pyruvate in the kidney, and cellular uptake of lactate and ketone bodies in neurons. It also transports the B-complex vitamin nicotinate. SLC5A12 is also localized to the apical membrane of epithelial cells lining the intestinal tract and proximal tubule. In the brain and retina, its expression is restricted to astrocytes and Müller cells. SLC5A8 also functions as a tumor suppressor; its expression is silenced in tumors of colon, thyroid, stomach, kidney, and brain. The tumor-suppressive function is related to its ability to mediate concentrative uptake of butyrate, propionate, and pyruvate, all of which are inhibitors of histone deacetylases. SLC5A8 can also transport a variety of pharmacologically relevant monocarboxylates, including salicylates, benzoate, and g-hydroxybutyrate. Non-steroidal anti-inflammatory drugs such as ibuprofen, ketoprofen, and fenoprofen, also interact with SLC5A8. These drugs are not transportable substrates for SLC5A8, but instead function as blockers of the transporter. Relatively less is known on the role of SLC5A12 in drug transport.

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

Cited by 121 publications

References 20 publications

Metabolic reprogramming of the tumor

Metabolic reprogramming of the tumor

Blockade of Dendritic Cell Development by Bacterial Fermentation Products Butyrate and Propionate through a Transporter (Slc5a8)-dependent Inhibition of Histone Deacetylases

Sodium-coupled Monocarboxylate Transporters in Normal Tissues and in Cancer

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