The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment

Brown, Timothy; Bhattacharjee, Pushpak; Ramachandran, Sabarish; Sivaprakasam, Sathish; Ristić, Bojana; Sikder, Mohd Omar Faruk; Ganapathy, Vadivel

doi:10.1038/s41388-020-1216-5

Cited by 185 publications

(165 citation statements)

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“…Although the impact of acidic microenvironment induced by lactate on tumorigenesis is well established, it has also become evident that lactate contributes to the tumor progression in many ways. In recent years, the studies from our lab and other labs has demonstrated that lactate plays a key role in immune evasion of cancer, this effect has been shown to be mediated in part through its ability to activate its receptor GPR81, which is highly expressed in cancer cells [13,16,38,39]. Furthermore, there is evidence of lactate as an alternative energy source to fuel oxidative tumor cells [40].…”

Section: Discussionmentioning

confidence: 89%

Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells

et al. 2020

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Background Metabolic reprogramming contributes significantly to tumor development and is tightly linked to drug resistance. The chemotherapeutic agent etoposide (VP-16) has been used clinically in the treatment of lung cancer but possess different sensitivity and efficacy towards SCLC and NSCLC. Here, we assessed the impact of etoposide on glycolytic metabolism in SCLC and NSCLC cell lines and investigated the role of metabolic rewiring in mediating etoposide resistance. Methods glycolytic differences of drug-treated cancer cells were determined by extracellular acidification rate (ECAR), glucose consumption, lactate production and western blot. DNA damage was evaluated by the comet assay and western blot. Chemoresistant cancer cells were analyzed by viability, apoptosis and western blot. Chromatin immunoprecipitation (ChIP) was used for analysis of DNA-protein interaction. Results Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1α-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer (NSCLC). We identified lactic acidosis as the key that confers multidrug resistance through upregulation of multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1), a member of ATP-binding cassette (ABC) transporter family. Mechanistically, lactic acid coordinates TGF-β1/Snail and TAZ/AP-1 pathway to induce formation of Snail/TAZ/AP-1 complex at the MRP1/ABCC1 promoter. Induction of MRP1 expression inhibits genotoxic and apoptotic effects of chemotherapeutic drugs by increasing drug efflux. Furthermore, titration of lactic acid with NaHCO3 was sufficient to overcome resistance. Conclusions The chemotherapeutic drug etoposide induces the shift toward aerobic glycolysis in the NSCLC rather than SCLC cell lines. The increased lactic acid in extracellular environment plays important role in etoposide resistance through upregulation of MRP expression. These data provide first evidence for the increased lactate production, upon drug treatment, contributes to adaptive resistance in NSCLC and reveal potential vulnerabilities of lactate metabolism and/or pathway suitable for therapeutic targeting. Graphical abstract

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Section: Discussionmentioning

confidence: 89%

Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells

et al. 2020

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“…Thus, high concentrations of lactate in the local environment of differentiating or maturing DCs induces tolerance in DCs, via altering metabolism and antigen processing ( Table 1 ). Extracellular lactate can mediate its anti-inflammatory function via binding to lactate receptor Gi-protein–coupled receptor 81 (GPR81) as was recently shown in DCs derived from murine mammary gland tumors ( 114 ). Alternatively, lactate can enter the cells via monocarboxylate transporter 1 (MCT1) as was shown in moDCs ( 92 ).…”

Section: Effects Of the Metabolic Environment On Dcs In Cancermentioning

confidence: 95%

Shaping of Dendritic Cell Function by the Metabolic Micro-Environment

Brombacher

Everts

2020

Front. Endocrinol.

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Nutrients are required for growth and survival of all cells, but are also crucially involved in cell fate determination of many cell types, including immune cells. There is a growing appreciation that the metabolic micro-environment also plays a major role in shaping the functional properties of dendritic cells (DCs). Under pathological conditions nutrient availability can range from a very restricted supply, such as seen in a tumor micro-environment, to an overabundance of nutrients found in for example obese adipose tissue. In this review we will discuss what is currently known about the metabolic requirements for DC differentiation and immunogenicity and compare that to how function and fate of DCs under pathological conditions can be affected by alterations in environmental levels of carbohydrates, lipids and amino acids as well as by other metabolic cues, including availability of oxygen, redox homeostasis and lactate levels. Many of these insights have been generated using in vitro model systems, which have revealed highly diverse effects of different metabolic cues on DC function. However, they also stress the importance of shifting toward more physiologically relevant experimental settings to be able to fully delineate the role of the metabolic surroundings in its full complexity in shaping the functional properties of DCs in health and disease.

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“…Differences in expression of the plasma membrane and mitochondrial transporters take part in the regulation of various metabolic pathways in the cytoplasm and mitochondria. Several transporters for specific nutrients and metabolites have been shown to be upregulated in cancer cells such as glucose, lactate or amino acids transporters (Ganapathy et al, 2009;Bhutia et al, 2015;El Ansari et al, 2018;Ma et al, 2018;Brown and Ganapathy, 2020;Brown et al, 2020b;Zhang and Li, 2020).…”

Section: Introductionmentioning

confidence: 99%

Extracellular Citrate Fuels Cancer Cell Metabolism and Growth

Haferkamp

Drexler

Federlin³

et al. 2020

Front. Cell Dev. Biol.

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Cancer cells need excess energy and essential nutrients/metabolites not only to divide and proliferate but also to migrate and invade distant organs for metastasis. Fatty acid and cholesterol synthesis, considered a hallmark of cancer for anabolism and membrane biogenesis, requires citrate. We review here potential pathways in which citrate is synthesized and/or supplied to cancer cells and the impact of extracellular citrate on cancer cell metabolism and growth. Cancer cells employ different mechanisms to support mitochondrial activity and citrate synthesis when some of the necessary substrates are missing in the extracellular space. We also discuss the different transport mechanisms available for the entry of extracellular citrate into cancer cells and how citrate as a master metabolite enhances ATP production and fuels anabolic pathways. The available literature suggests that cancer cells show an increased metabolic flexibility with which they tackle changing environmental conditions, a phenomenon crucial for cancer cell proliferation and metastasis.

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The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment

Cited by 185 publications

References 44 publications

Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells

Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells

Shaping of Dendritic Cell Function by the Metabolic Micro-Environment

Extracellular Citrate Fuels Cancer Cell Metabolism and Growth

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