Lactate/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon

Brown, Timothy; Ganapathy, Vadivel

doi:10.1016/j.pharmthera.2019.107451

Cited by 237 publications

(184 citation statements)

References 140 publications

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“…As a crucial lactate receptor, GPR81 directly affects metabolites involved in tumor cell survival and energy metabolism, altering the uptake of glucose and modulating the normal process in mammalian organisms by activating various receptors ( 28 ). A similar observation regarding the role of GPR81 was made in breast cancer and pancreatic carcinoma cell lines ( 29 , 30 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of GPR81 silencing combined with cisplatin stimulation on biological function in hypopharyngeal squamous cell carcinoma

Jia

Dong

et al. 2020

Mol Med Rep

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Hypopharyngeal squamous cell carcinoma (HSCC) is a malignant tumor found in the head and neck region. Lactate receptor 1, also known as G protein-coupled receptor81 (GPR81), has been reported to play a vital role in cancer growth and metabolism. However, the function of GPR81 in HSCC remains largely unknown. The present study investigated the effect of GPR81 on cell survival and GPR81-mediated energy metabolism under cisplatin treatment in HSCC. GPR81 knockdown reduced the proliferation and invasion of the human HSCC cell line FaDu. Furthermore, GPR81 silencing combined with cisplatin treatment increased the expression of translocase of outer mitochondrial membrane 20 at the mRNA and protein levels (P<0.05). mRNA and protein expression of phosphofructokinase 1 in mRNA appeared to be downregulated in GPR81 knockdown FaDu cells treated with cisplatin, although this was not statistically significant. GPR81 silencing and cisplatin challenge showed no significant upregulation compared with the control, but significant downregulation in mRNA and protein levels compared with the shRNA-scramble group. Apoptosis was measured by flow cytometry with annexin V and 7-aminoactinomycin D. GPR81 silencing and cisplatin led to an increased apoptotic rate. Moreover, absence of GPR81 combined with cisplatin exposure increased caspase-3 expression and decreased Bcl-2 levels. The results of the present study suggested that GPR81 and cisplatin sensitivity played an important role in HSCC growth and metabolism.

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Section: Discussionmentioning

confidence: 99%

Effects of GPR81 silencing combined with cisplatin stimulation on biological function in hypopharyngeal squamous cell carcinoma

Jia

Dong

et al. 2020

Mol Med Rep

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“…High content of lactate and choline, and low levels of citrate, glutamine, and glutamate were reported by Ryoo et al [27] in malignant thyroid nodules, and were suggested as the discriminative markers for determining the preoperative metabolomic profile of thyroid nodules. High levels of lactate have also been found in several other neoplasias, including breast, glioma, and head and neck cancers [28]. Elevated levels of lactate result from an increase in the glycolytic pathway following hypoxia or ischemia in tumor tissues.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Reprogramming Detected by 1H-NMR Spectroscopy in Human Thyroid Cancer Tissues

Metere

Graves

Chirico

et al. 2020

Biology

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Thyroid cancer cells demonstrate an increase in oxidative stress and decreased antioxidant action, but the effects of this increased oxidative stress on cell function remain unknown. We aimed to identify changes in the metabolism of thyroid cancer cells caused by oxidative stress, using proton nuclear magnetic resonance (1H-NMR) spectroscopy. Samples of thyroid cancer and healthy thyroid tissue were collected from patients undergoing thyroidectomy and analyzed with 1H-NMR spectroscopy for a wide array of metabolites. We found a significant increase in lactate content in thyroid cancer tissue compared to healthy tissue. Metabolomic analysis demonstrated significant differences between cancer tissue and healthy tissue, including an increase in aromatic amino acids, and an average decrease in citrate in thyroid cancer tissue. We hypothesize that these changes in metabolism may be due to an oxidative stress-related decrease in activity of the Krebs cycle, and a shift towards glycolysis in cancer tissue. Thus, thyroid cancer cells are able to reprogram their metabolic activity to survive in conditions of high oxidative stress and with a compromised antioxidant system. Our findings, for the first time, suggested a connection between oxidative stress and the alteration of the metabolic profile in thyroid tumors.

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“…In summary, all the reported evidences support a pro-cancerous role of the lactate-HCAR1 pathway and point to the blockade of this receptor as a potential anti-neoplastic strategy but unfortunately, no antagonists or blocking antibodies are available to be tested in this setting at present [79].…”

Section: Gpr81/hca 1 Receptormentioning

confidence: 99%

Metabolite Sensing GPCRs: Promising Therapeutic Targets for Cancer Treatment?

Cosín-Roger

Ortiz-Masiá

Barrachina

et al. 2020

Cells

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G-protein-coupled receptors constitute the most diverse and largest receptor family in the human genome, with approximately 800 different members identified. Given the well-known metabolic alterations in cancer development, we will focus specifically in the 19 G-protein-coupled receptors (GPCRs), which can be selectively activated by metabolites. These metabolite sensing GPCRs control crucial processes, such as cell proliferation, differentiation, migration, and survival after their activation. In the present review, we will describe the main functions of these metabolite sensing GPCRs and shed light on the benefits of their potential use as possible pharmacological targets for cancer treatment.

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Lactate/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon

Cited by 237 publications

References 140 publications

Effects of GPR81 silencing combined with cisplatin stimulation on biological function in hypopharyngeal squamous cell carcinoma

Effects of GPR81 silencing combined with cisplatin stimulation on biological function in hypopharyngeal squamous cell carcinoma

Metabolomic Reprogramming Detected by 1H-NMR Spectroscopy in Human Thyroid Cancer Tissues

Metabolite Sensing GPCRs: Promising Therapeutic Targets for Cancer Treatment?

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