Extracellular ATP a New Player in Cancer Metabolism: NSCLC Cells Internalize ATP <i>In Vitro</i> and <i>In Vivo</i> Using Multiple Endocytic Mechanisms

Qian, Yanrong; Wang, Xuan; Li, Yunsheng; Cao, Yanyang; Chen, Xiaozhuo

doi:10.1158/1541-7786.mcr-16-0118

Cited by 83 publications

(96 citation statements)

References 46 publications

(88 reference statements)

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“…ATP is known as the main energy fuel and also reported to promote cell proliferation and drug resistance in cancer cells. 61 Because we have observed inverse association between DMT1 and oxidative phosphorylation, our results might indicate that DMT1 plays a role in directly or indirectly inhibiting oxidative phosphorylation or vice versa. Indeed, our findings of strong correlation between increased mitochondrial metabolism and worse prognosis are in line with the profound influence of mitochondrial metabolism on all steps of oncogenesis such as malignant transformation, tumor progression, and response to treatment.…”

Section: Discussionmentioning

confidence: 57%

Low DMT1 Expression Associates With Increased Oxidative Phosphorylation and Early Recurrence in Hepatocellular Carcinoma

Hoki

Katsuta

Yan

et al. 2019

Journal of Surgical Research

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Background: Despite a high rate of recurrences, long-term survival can be achieved after the resection of hepatocellular carcinoma (HCC) with effective local treatment. Discovery of adverse prognostic variables to identify patients with high risk of recurrence could improve the management of HCC. Accumulating evidence showing a link between carcinogenesis and increased expression of iron import proteins and intracellular iron prompted us to investigate a role of divalent metal-ion transporter-1 (DMT1) that binds and regulates a variety of divalent metals in HCC. Materials and methods: Clinical and gene expression data from RNA seq in 369 HCC patients were obtained from The Cancer Genome Atlas. Disease-free survival was compared between DMT1 high-and low-expressing tumors, and gene set enrichment analysis was conducted. Results: Patients with lower expression of DMT1 exhibited significantly worse disease-free survival compared with the DMT1 high group (P ¼ 0.044), notably in advanced-stage patients (P ¼ 0.008). DMT1 expression did not differ in etiologies, stages, and differentiation status of HCC. Interestingly, DMT1 expression levels inversely associated with cellular respiratory function in HCC. Furthermore, gene set enrichment analysis revealed that metabolism-related gene sets such as glycolysis, oxidative phosphorylation, and reactive oxygen species pathway were significantly enriched in the DMT1 low-expressing HCC.

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Section: Discussionmentioning

confidence: 57%

Low DMT1 Expression Associates With Increased Oxidative Phosphorylation and Early Recurrence in Hepatocellular Carcinoma

Hoki

Katsuta

Yan

et al. 2019

Journal of Surgical Research

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“…To understand why T255V mutation inhibits cell proliferation, we first supplemented 3-PG and ATP 30,31 , the primary products of PGK1-catalyzed reaction in the culture medium, which resulted in a partial rescue of the cell proliferation ( Fig. 4c).…”

Section: Articlementioning

confidence: 99%

O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth

et al. 2020

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Many cancer cells display enhanced glycolysis and suppressed mitochondrial metabolism. This phenomenon, known as the Warburg effect, is critical for tumor development. However, how cancer cells coordinate glucose metabolism through glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle is largely unknown. We demonstrate here that phosphoglycerate kinase 1 (PGK1), the first ATP-producing enzyme in glycolysis, is reversibly and dynamically modified with O-linked N-acetylglucosamine (O-GlcNAc) at threonine 255 (T255). O-GlcNAcylation activates PGK1 activity to enhance lactate production, and simultaneously induces PGK1 translocation into mitochondria. Inside mitochondria, PGK1 acts as a kinase to inhibit pyruvate dehydrogenase (PDH) complex to reduce oxidative phosphorylation. Blocking T255 O-GlcNAcylation of PGK1 decreases colon cancer cell proliferation, suppresses glycolysis, enhances the TCA cycle, and inhibits tumor growth in xenograft models. Furthermore, PGK1 O-GlcNAcylation levels are elevated in human colon cancers. This study highlights O-GlcNAcylation as an important signal for coordinating glycolysis and the TCA cycle to promote tumorigenesis.

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“…Recently, ATP deregulation has been reported related to tumor growth. It was found that extracellular ATP in cancer cells can be internalized by macropiocytosis and caveolae-/clathrin-mediated ecdocytosis, leading to ATP concentration increase by 1000 times higher than those in normal tissues (Qian et al, 2014(Qian et al, , 2016. Evidences indicated that extracellular ATP accumulation increases glycogen stores, cytosolic Ca 2þ and Bcl-2/ Bax and mitochondrial biosynthesis, and plays a pivotal role in resistance to chemotherapy, as found in colon cancer (Zhou et al, 2012), cell survival (lung cancer) (Song et al, 2016), and metastases (prostate cancer, through activating Rho GTPase and MMPs) (Zhang et al, 2010).…”

Section: Atp and Cancersmentioning

confidence: 99%

Mechanisms of AMPK in the maintenance of ATP balance during energy metabolism

Liu

et al. 2018

Cell Biology International

265

175

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AMP-activated protein kinase (AMPK) is a conserved sensor of cellular energy change and is activated by increased AMP/ATP and/or ADP/ATP ratios. AMPK maintains the energy balance by decreasing the ATP-consuming processes such as transcription of synthetic fat genes and rRNA, the translation of ribosomal proteins, synthesis of cholesterol and fatty acid, while the metabolic pathways such as glucose and fatty transport, fatty acid oxidation, autophagy, mitochondrial synthesis and oxidative metabolism are increased to preserve ATP during energy deficiency. Recent advance has demonstrated that AMPK activity has a close association with the initiation and progression in various cancers. Here we review the mechanisms that AMPK controls energy metabolism through regulating ATP synthesis and consumption, and further discuss the deregulation of AMPK in cancers.

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Extracellular ATP a New Player in Cancer Metabolism: NSCLC Cells Internalize ATP In Vitro and In Vivo Using Multiple Endocytic Mechanisms

Cited by 83 publications

References 46 publications

Low DMT1 Expression Associates With Increased Oxidative Phosphorylation and Early Recurrence in Hepatocellular Carcinoma

Low DMT1 Expression Associates With Increased Oxidative Phosphorylation and Early Recurrence in Hepatocellular Carcinoma

O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth

Mechanisms of AMPK in the maintenance of ATP balance during energy metabolism

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