Nutrient transporters in cancer: Relevance to Warburg hypothesis and beyond

Ganapathy, Vadivel; Thangaraju, Muthusamy; Prasad, Puttur D.

doi:10.1016/j.pharmthera.2008.09.005

Cited by 630 publications

(592 citation statements)

References 133 publications

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“…6,8). Here, we have shown that the endosomal protein HRG-1/ SLC48A1 is a new IGF-I-regulated protein that may enhance the proliferative and invasive phenotype of cancer cells through its effects on endosomal acidification and receptor trafficking.…”

Section: Discussionmentioning

confidence: 95%

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Heme-binding Protein HRG-1 Is Induced by Insulin-like Growth Factor I and Associates with the Vacuolar H+-ATPase to Control Endosomal pH and Receptor Trafficking

O’Callaghan

Ayllón

O'Keeffe

et al. 2010

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 95%

“…The expression levels and trafficking of nutrient transporters are tightly regulated by growth factors, especially through activity of the insulin/IGF-I 3 -activated PI3K/mammalian target of rapamycin signaling pathway (7). Both overexpression of nutrient transporters and decreased degradation in lysosomes have been linked to cellular transformation (7,8).…”

mentioning

confidence: 99%

Heme-binding Protein HRG-1 Is Induced by Insulin-like Growth Factor I and Associates with the Vacuolar H+-ATPase to Control Endosomal pH and Receptor Trafficking

O’Callaghan

Ayllón

O'Keeffe

et al. 2010

Journal of Biological Chemistry

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“…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).…”

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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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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“…Thus, Glut1 and ASCT2 are key to cell proliferation and oncogenic processes; this has been an ongoing research field for Glut1 (or SLC2A1) since Warburg's genial work in the 1950s 4 and ASCT2 (or SLC1A5) is a transporter of neutral amino acids regulating proliferation versus autophagy associated to mTOR pathways and corresponding mTOR complexes. 33 PiT1 and PiT2 are inorganic phosphate transporters 31 and, interestingly, PiT1 has been shown to regulate cell proliferation independently of phosphate transport.…”

Section: Discussionmentioning

confidence: 99%

“…While metabolomics relies mainly on the quantification of anabolic and catabolic end products, 3 the bidirectional fluxes of nutrients and metabolites, as well as the efflux of toxins and pharmaceutical compounds, are ensured by nutrient transporters. 4 However, the monitoring of metabolite and nutrient transporters at the cell surface has been hampered by the paucity, if not total lack, of exofacial antibodies to such transporters. 5,6 Cell entry of gamma-and deltaretroviruses occurs via recognition of membrane metabolite transporters by retroviral envelope glycoproteins (Env).…”

mentioning

confidence: 99%

Optimization of tumor xenograft dissociation for the profiling of cell surface markers and nutrient transporters

Petit

Massonnet

Maciorowski

et al. 2013

Laboratory Investigation

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Metabolic adaptations and changes in the expression of nutrient transporters are known to accompany tumorigenic processes. Nevertheless, in the context of solid tumors, studies of metabolism are hindered by a paucity of tools allowing the identification of cell surface transporters on individual cells. Here, we developed a method for the dissociation of human breast cancer tumor xenografts combined with quantification of cell surface markers, including metabolite transporters. The expression profiles of four relevant nutrient transporters for cancer cells' metabolism, Glut1, ASCT2, PiT1 and PiT2 (participating to glucose, glutamine and inorganic phosphate, respectively), as detected by new retroviral envelope glycoprotein-derived ligands, were distinctive of each tumor, unveiling underlying differences in metabolic pathways. Our tumor dissociation procedure and nutrient transporter profiling technology provides opportunities for future basic research, clinical diagnosis, prognosis and evaluation of therapeutic responses, as well as for drug discovery and development. Markers of tumor cell metabolism are of valuable importance for basic and clinical cancer research. The identification of metabolic alterations that accompany cancer processes is becoming critical for refining the clinical evaluation and treatment of patients, 1,2 as well as for further drug discovery and development. While metabolomics relies mainly on the quantification of anabolic and catabolic end products, 3 the bidirectional fluxes of nutrients and metabolites, as well as the efflux of toxins and pharmaceutical compounds, are ensured by nutrient transporters. 4 However, the monitoring of metabolite and nutrient transporters at the cell surface has been hampered by the paucity, if not total lack, of exofacial antibodies to such transporters. 5,6 Cell entry of gamma-and deltaretroviruses occurs via recognition of membrane metabolite transporters by retroviral envelope glycoproteins (Env). 7,8 Viral entry occurs following the specific binding of the amino-terminal receptor binding domain (RBD) of an individual Env with its cognate receptor. We designed RBD probes, derived from gamma-and deltaretroviral Env, as specific ligands that bind to these cell surface transporters. Binding of defined ligands allows the quantification of distinct sets of metabolite transporters at the cell surface. 9-13 Furthermore, while cell surface labeling is readily achieved on cultured cell lines and circulating hematopoietic cells, singlecell labeling of solid tumors has remained problematic. Indeed, such analyses require dissociation methods that yield

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Nutrient transporters in cancer: Relevance to Warburg hypothesis and beyond

Cited by 630 publications

References 133 publications

Heme-binding Protein HRG-1 Is Induced by Insulin-like Growth Factor I and Associates with the Vacuolar H+-ATPase to Control Endosomal pH and Receptor Trafficking

Heme-binding Protein HRG-1 Is Induced by Insulin-like Growth Factor I and Associates with the Vacuolar H+-ATPase to Control Endosomal pH and Receptor Trafficking

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

Optimization of tumor xenograft dissociation for the profiling of cell surface markers and nutrient transporters

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