Metformin Promotes 2-Deoxy-2-[18F]Fluoro-D-Glucose Uptake in Hepatocellular Carcinoma Cells Through FoxO1-Mediated Downregulation of Glucose-6-Phosphatase

Wang, Zhengjie; Kang, Fei; Gao, Yuan; Liu, Yi; Xu, Xiaolong; Ma, Xiaowei; Ma, Wenhui; Yang, Weidong; Wang, Jing

doi:10.1007/s11307-017-1150-2

Cited by 8 publications

(4 citation statements)

References 37 publications

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“…Mice were treated with normal saline (Con) and MOTS-c (5 mg/kg, per day) for long term (45 days) under room temperature, then mice were allowed to fast six hours and were anesthetized with isoflurane followed by a tail vein injection of 18F-FDG (120 mCi). Thirty mins after the injection of the 18F-FDG, the mice were subjected to PET/CT image test and analysis according to Wang Z. et al [37].…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation

Tang

Xue

et al. 2019

IJMS

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Cold exposure stress causes hypothermia, cognitive impairment, liver injury, and cardiovascular diseases, thereby increasing morbidity and mortality. Paradoxically, cold acclimation is believed to confer metabolic improvement to allow individuals to adapt to cold, harsh conditions and to protect them from cold stress-induced diseases. However, the therapeutic strategy to enhance cold acclimation remains less studied. Here, we demonstrate that the mitochondrial-derived peptide MOTS-c efficiently promotes cold adaptation. Following cold exposure, the improvement of adipose non-shivering thermogenesis facilitated cold adaptation. MOTS-c, a newly identified peptide, is secreted by mitochondria. In this study, we observed that the level of MOTS-c in serum decreased after cold stress. MOTS-c treatment enhanced cold tolerance and reduced lipid trafficking to the liver. In addition, MOTS-c dramatically upregulated brown adipose tissue (BAT) thermogenic gene expression and increased white fat “browning”. This effect might have been mediated by MOTS-c-activated phosphorylation of the ERK signaling pathway. The inhibition of ERK signaling disturbed the up-regulatory effect of MOTS-c on thermogenesis. In summary, our results indicate that MOTS-c treatment is a potential therapeutic strategy for defending against cold stress by increasing the adipose thermogenesis via the ERK pathway.

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Section: Methodsmentioning

confidence: 99%

Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation

Tang

Xue

et al. 2019

IJMS

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“…For example, 2-DG is an analog of glucose, and it can be catalyzed by HK2 into 2-deoxy-D-glucose-6-phosphate (2-DG-6P), which is different from G-6-P and can noncompetitively inhibit the activity of HK2 [5,35]. When 2-DG was given alone in HCC, it was reported to suppress the growth, metastasis and invasion of HCC cells, and the combination treatment of 2-DG and other chemotherapy drugs, such as sorafenib, 2aminophenoxazine-3-one (Phx-3), and metformin, can also enhance the anticancer effect of them on HCC [179][180][181]. The 3-bromopyruvate (3-BP) is a different type of HK2 inhibitor with the ability to inhibit HK2 activity directly, so as to strongly suppress the glycolysis process.…”

Section: Therapeutic Agents That Target Glycolysismentioning

confidence: 99%

Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma

Jiao

et al. 2020

J Exp Clin Cancer Res

378

305

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Liver cancer has become the sixth most diagnosed cancer and the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is responsible for up to 75–85% of primary liver cancers, and sorafenib is the first targeted drug for advanced HCC treatment. However, sorafenib resistance is common because of the resultant enhancement of aerobic glycolysis and other molecular mechanisms. Aerobic glycolysis was firstly found in HCC, acts as a hallmark of liver cancer and is responsible for the regulation of proliferation, immune evasion, invasion, metastasis, angiogenesis, and drug resistance in HCC. The three rate-limiting enzymes in the glycolytic pathway, including hexokinase 2 (HK2), phosphofructokinase 1 (PFK1), and pyruvate kinases type M2 (PKM2) play an important role in the regulation of aerobic glycolysis in HCC and can be regulated by many mechanisms, such as the AMPK, PI3K/Akt pathway, HIF-1α, c-Myc and noncoding RNAs. Because of the importance of aerobic glycolysis in the progression of HCC, targeting key factors in its pathway such as the inhibition of HK2, PFK or PKM2, represent potential new therapeutic approaches for the treatment of HCC.

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“…It is reported that higher FDG uptake, higher GLUT1 expression and lower G6Pase expression are greater in poorly differentiated HCC than moderately differentiated HCC [11,20]. Among the 12 cases in which extrahepatic metastasis recurred, 1 had a TNR < 1.53.…”

Section: Discussionmentioning

confidence: 99%

Preoperative PET-CT is useful for predicting recurrent extrahepatic metastasis of hepatocellular carcinoma after resection

Morio

Kawaoka

Aikata

et al. 2020

European Journal of Radiology

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In recent years, it has been reported that use of 18 F-FDG PET-CT can reveal the degree of hepatocellular carcinoma malignancy. We evaluate the ability of a preoperative 18 F-FDG PET-CT to predict the recurrence of extrahepatic metastasis after surgery. Methods:We retrospectively examined 67 patients who received 18 F-FDG PET-CT prior to curative hepatic resection between April 2010 and March 2016. Multivariate Cox regression analysis was performed to identify the factors associated with recurrence of extrahepatic metastasis after surgery. We also evaluated the sensitivity, specifity, positive predictive value, negative predictive value and accuracy of diagnosis of 18 F-FDG PET-CT for recurrent extrahepatic metastasis after surgery. Results:The multivariate analysis identified a tumor-to-normal liver standardized uptake value ratio (TNR) ≥ 1.53 (hazard ratio [HR], 0.037; P = 0.003), multiple tumor nodules (HR, 0.121; P = 0.007), and presence of microvascular invasion (HR, 0.094; P = 0.003) as independent predictors of distant metastasis recurrence. A TNR ≥ 1.53 showed a sensitivity of 91.7%, specificity of 76.4%, positive predictive value of 45.8%, negative predictive value of 97.7%, and accuracy of 79.1% for diagnosing distant metastasis recurrence. In a binomial logistic regression analysis of tumor factors associated with a TNR ≥ 1.53, poor tumor differentiation and large tumor size were significant factors. Conclusion:18 F-FDG PET-CT and microvascular invasion may be useful for predicting the recurrence of extrahepatic metastasis after surgery.

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Metformin Promotes 2-Deoxy-2-[18F]Fluoro-D-Glucose Uptake in Hepatocellular Carcinoma Cells Through FoxO1-Mediated Downregulation of Glucose-6-Phosphatase

Abstract: We propose that treatment of HCC cells with Met may be a useful strategy for improving the efficacy of [F]FDG as a tracer for PET/CT imaging of HCC tumors in patients.

Cited by 8 publications

References 37 publications

Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation

Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation

Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma

Preoperative PET-CT is useful for predicting recurrent extrahepatic metastasis of hepatocellular carcinoma after resection

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