Abstract:BackgroundLigand-dependent activation of the G-protein coupled receptor 119 (GPR119) lowers blood glucose via glucose-dependent insulin secretion and intestinal glucagon-like peptide-1 production. However, the function of GPR119 in cancer cells has not been studied.MethodsGPR119 expression was assessed by real-time qPCR and immunohistochemistry in human breast cancer cell lines and breast cancer tissues. Cell proliferation and cell cycle analyses were performed by Incucyte® live cell analysis system and flow c… Show more
“…Lactate may be a potential and critical contributory factor in the regulation of immune function in sepsis. It has been reported that increased production of lactate suppressed autophagy in cancer cells (41). In the present study, it was revealed that lactate treatment decreased the autophagy marker LC3-II and increased p62 in the HK-2 cells stimulated with LPS.…”
Metabolism reprogramming influences the severity of organ dysfunction, progression to fibrosis, and development of disease in acute kidney injury (AKI). Previously we showed that inhibition of aerobic glycolysis improved survival rates and protected septic mice from kidney injury. However, the underlying mechanisms remain unclear. In the present study, it was revealed that sepsis or lipopolysaccharide (LPS) enhanced aerobic glycolysis as evidenced by increased lactate production and upregulated mRNA expression of glycolysis-related genes in kidney tissues and human renal tubular epithelial (HK-2) cells. The aerobic glycolysis inhibitor 2-deoxy-D-glucose (2-DG) downregulated glycolysis, and improved kidney injury induced by sepsis. 2-DG treatments increased the expression of sirtuin 3 (SIRT3) and phosphorylation-AMP-activated protein kinase (p-AMPK), following promoted autophagy and attenuated apoptosis of tubular epithelial cells in septic mice and in LPS-treated HK-2 cells. However, the glycolysis metabolite lactate downregulated SIRT3 and p-AMPK expression, inhibited autophagy and enhanced apoptosis in LPS-treated HK-2 cells. Furthermore, pharmacological blockade of autophagy with 3-methyladenine (3-MA) partially abolished the protective effect of 2-DG in sepsis-induced AKI. These findings indicated that inhibition of aerobic glycolysis protected against sepsis-induced AKI by promoting autophagy via the lactate/SIRT3/AMPK pathway.
“…Lactate may be a potential and critical contributory factor in the regulation of immune function in sepsis. It has been reported that increased production of lactate suppressed autophagy in cancer cells (41). In the present study, it was revealed that lactate treatment decreased the autophagy marker LC3-II and increased p62 in the HK-2 cells stimulated with LPS.…”
Metabolism reprogramming influences the severity of organ dysfunction, progression to fibrosis, and development of disease in acute kidney injury (AKI). Previously we showed that inhibition of aerobic glycolysis improved survival rates and protected septic mice from kidney injury. However, the underlying mechanisms remain unclear. In the present study, it was revealed that sepsis or lipopolysaccharide (LPS) enhanced aerobic glycolysis as evidenced by increased lactate production and upregulated mRNA expression of glycolysis-related genes in kidney tissues and human renal tubular epithelial (HK-2) cells. The aerobic glycolysis inhibitor 2-deoxy-D-glucose (2-DG) downregulated glycolysis, and improved kidney injury induced by sepsis. 2-DG treatments increased the expression of sirtuin 3 (SIRT3) and phosphorylation-AMP-activated protein kinase (p-AMPK), following promoted autophagy and attenuated apoptosis of tubular epithelial cells in septic mice and in LPS-treated HK-2 cells. However, the glycolysis metabolite lactate downregulated SIRT3 and p-AMPK expression, inhibited autophagy and enhanced apoptosis in LPS-treated HK-2 cells. Furthermore, pharmacological blockade of autophagy with 3-methyladenine (3-MA) partially abolished the protective effect of 2-DG in sepsis-induced AKI. These findings indicated that inhibition of aerobic glycolysis protected against sepsis-induced AKI by promoting autophagy via the lactate/SIRT3/AMPK pathway.
“…Thus, lactate sustains constitutively high levels of active Rheb and, in turn, constitutively active mTORC1. Although surprising, this is consistent with a recent report showing that autophagy, which is suppressed by mTORC1, can be inhibited by lactate [4]. Lactate administration has also been shown to activate mTORC1 in muscle of adult mice [5].…”
The kinase mammalian target of rapamycin (mTOR) is a major regulatory hub that senses and integrates nutrient, energy, and growth factor inputs to promote cell growth. In this issue of EMBO Reports, Byun et al [1] report that high intracellular levels of lactate activate mTORC1 in KRAS transformed cells independently of a growth factor input. This suggests a mechanism for how mTORC1 can be co‐opted to support oncogenic growth and proliferation.
“…However, GPR119 is only activated by eCBs analogues, including oleoylethanolamide and palmitoylethanolamide, rather than pCBs or sCBs. Therefore, GPR119 is not discussed in detail here, other than to outline that its agonism by specific ligands (such as MBX-2982 or GSK1292263), re-sensitises breast cancer cells that have developed resistance to gefitinib [74]. Uniquely, CBD is a ligand for the orphan GPCRs, GPR3, GPR6 and GPR12 (discussed in Section 3.2.3).…”
Section: Non-thc Cannabinoids Are Ligands For Calcium Selective Ion Channels and Orphaned/de-orphaned G-protein-coupled Receptorsmentioning
Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited by the psychotropic side effects of ∆9-tetrahydrocannabinol (∆9-THC). Evidence is emerging for the therapeutic benefits of cannabis in the treatment of neurological and neurodegenerative diseases, with potential efficacy as an analgesic and antiemetic for the management of cancer-related pain and treatment-related nausea and vomiting, respectively. An increasing number of preclinical studies have established that ∆9-THC can inhibit the growth and proliferation of cancerous cells through the modulation of cannabinoid receptors (CB1R and CB2R), but clinical confirmation remains lacking. In parallel, the anti-cancer properties of non-THC cannabinoids, such as cannabidiol (CBD), are linked to the modulation of non-CB1R/CB2R G-protein-coupled receptors, neurotransmitter receptors, and ligand-regulated transcription factors, which together modulate oncogenic signalling and redox homeostasis. Additional evidence has also demonstrated the anti-inflammatory properties of cannabinoids, and this may prove relevant in the context of peritumoural oedema and the tumour immune microenvironment. This review aims to document the emerging mechanisms of anti-cancer actions of non-THC cannabinoids.
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