Metformin attenuates hepatoma cell proliferation by decreasing glycolytic flux through the HIF-1α/PFKFB3/PFK1 pathway

Hu, La; Zeng, Zicheng; Xia, Qing; Liu, Zhaoyu; Xiao, Feng; Chen, Jitao; Huang, Mengqiu; Chen, Liangcai; Fang, Zhiyuan; Liu, Qiuzhen; Zeng, Hongbo; Zhou, Xinke; Liu, Jifang

doi:10.1016/j.lfs.2019.116966

Cited by 60 publications

(47 citation statements)

References 41 publications

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“…Metformin, as a well-tolerated traditional first-line antihyperglycemic drug for diabetes, has recently been found to have therapeutic effects in obesity, non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome (29,30). Besides, metformin alone or combined with other chemotherapy drugs exhibits an obvious inhibition effect on the malignant properties of various cancers including HCC (3,5,31,32). Our data also revealed that metformin at appropriate concentrations obviously suppressed proliferation, motility, invasion and metastasis of HCC cells.…”

Section: Discussionmentioning

confidence: 99%

“…Type 2 diabetes patients treated with metformin have a lower risk for HCC development compared with those taking other antidiabetic drugs in a large populationbased prospective clinical epidemiological survey (1). Besides, metformin alone or combined with other drugs obviously counteracts malignant features of HCC through multiple mechanisms (2)(3)(4)(5), suggesting an obvious antitumor role of metformin in HCC development and progression. Similar to other chemotherapy drugs, metformin may be also developed into drug tolerance and resistance in HCC during long-term treatment.…”

Section: Introductionmentioning

confidence: 99%

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Matrix Stiffness-Upregulated MicroRNA-17-5p Attenuates the Intervention Effects of Metformin on HCC Invasion and Metastasis by Targeting the PTEN/PI3K/Akt Pathway

et al. 2020

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Background: Metformin, a traditional first-line anti-hyperglycemic agent for diabetes, recently exhibits better antitumor effect in hepatocellular carcinoma (HCC). However, its resistance and tolerance mechanism in HCC remains largely unknown. Here, we investigated whether increased matrix stiffness attenuated the intervention effects of metformin on HCC invasion and metastasis, and explored its underlying molecular mechanism. Methods: FN-coated gel substrates with 6, 10, and 16 kPa, which simulated the stiffness of normal, fibrotic, and cirrhotic liver tissues respectively, were established to evaluate matrix stiffness-mediated effects on HCC cells. Alterations in morphology, proliferation, motility, and invasive/metastatic-associated genes (PTEN, MMP2, MMP9) of HCC cells grown on different-stiffness substrates were comparatively analyzed before and after metformin intervention. Subsequently, the underlying molecular mechanism by which higher matrix stiffness attenuates antitumor effects of metformin in HCC was further elucidated. Results: Metformin significantly inhibited proliferation, migration, and invasion of HCC cells. Compared with the controls on lower-stiffness substrate, HCC cells grown on higher-stiffness substrate exhibited an obvious resistance to intervention effects of metformin on proliferation, migration, invasion and metastasis. High stiffness stimulation significantly activated the miR-17-5p/PTEN/PI3K/Akt signaling pathway in HCC cells via integrin β1 and in turn resulted in MMP2 and MMP9 upregulation. Meanwhile, integrin β1 knockdown or PI3K inhibitor partially reversed the activation of the above signaling molecules. For HCC cells grown on the same-stiffness substrate, metformin remarkably upregulated PTEN expression and suppressed the activation of the PI3K/Akt/MMP pathway, but no effect on integrin β1 expression. Importantly, the increase in fold of PTEN expression and decrease in folds of Akt phosphorylation level and MMP2

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Matrix Stiffness-Upregulated MicroRNA-17-5p Attenuates the Intervention Effects of Metformin on HCC Invasion and Metastasis by Targeting the PTEN/PI3K/Akt Pathway

et al. 2020

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“…Among the ten cancer hallmarks proposed by Weinberg and Hanahan, 3 metabolic reprogramming is highlighted as an important aspect in cancer treatment. 4 , 5 Various small molecules that target different pathways involved in cancer metabolism have now been identified, 6 , 7 with some already undergoing clinical trials. 8 Unexpectedly, the efficacy of many metabolism-targeting drugs is inadequate.…”

Section: Introductionmentioning

confidence: 99%

Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference

Kuo

Huang

Yang

et al. 2020

Molecular Therapy - Oncolytics

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Targeting metabolic reprogramming is an emerging strategy in cancer therapy. However, clinical attempts to target metabolic reprogramming have been proved to be challenging, with metabolic heterogeneity of cancer being one of many reasons that causes treatment failure. Here, we stratified non-small cell lung cancer (NSCLC) cells, mainly lung adenocarcinoma, based on their metabolic phenotypes and demonstrated that the aerobic glycolysis-preference NSCLC cell subtype was resistant to the OXPHOS-targeting inhibitors. We identified that monocarboxylate transporter 4 (MCT4), a lactate transporter, was highly expressed in the aerobic glycolysis-preference subtype with function supporting the proliferation of these cells. Glucose could induce the expression of MCT4 in these cells through a DNp63a and Sp1-dependent pathway. Next, we showed that knockdown of MCT4 increased intracellular lactate concentration and induced a reactive oxygen species (ROS)-dependent cellular apoptosis in the aerobic glycolysispreference NSCLC cell subtype. By scanning a panel of monoclonal antibodies with MCT4 neutralizing activity, we further identified a MCT4 immunoglobulin M (IgM) monoclonal antibody showing capable anti-proliferation efficacy on the aerobic glycolysis-preference NSCLC cell subtype. Our findings indicate that the metabolic heterogeneity is a critical factor for NSCLC therapy and manipulating the expression or function of MCT4 can be an effective strategy in targeting the aerobic glycolysis-preference NSCLC cell subtype.

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“…209 Metformin can target the HIF-1α/PFKFB3/PFK1 pathway in hepatoma cells and reduce hepatoma cell proliferation by inhibiting glycolysis. 210 Pyruvate kinase (PK) is the third rate-limiting enzyme in glycolysis. It has multiple subtypes, among which PKM2 is upregulated in a variety of cancers.…”

Section: Treatments For Aerobic Glycolysismentioning

confidence: 99%

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

Tian

Zhu

et al. 2020

CMAR

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Hepatocellular carcinoma (HCC) is a tumor that exhibits glucometabolic reprogramming, with a high incidence and poor prognosis. Usually, HCC is not discovered until an advanced stage. Sorafenib is almost the only drug that is effective at treating advanced HCC, and promising metabolism-related therapeutic targets of HCC are urgently needed. The "Warburg effect" illustrates that tumor cells tend to choose aerobic glycolysis over oxidative phosphorylation (OXPHOS), which is closely related to the features of the tumor microenvironment (TME). The HCC microenvironment consists of hypoxia, acidosis and immune suppression, and contributes to tumor glycolysis. In turn, the glycolysis of the tumor aggravates hypoxia, acidosis and immune suppression, and leads to tumor proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), invasion and metastasis. In 2017, a mechanism underlying the effects of gluconeogenesis on inhibiting glycolysis and blockading HCC progression was proposed. Treating HCC by increasing gluconeogenesis has attracted increasing attention from scientists, but few articles have summarized it. In this review, we discuss the mechanisms associated with the TME, glycolysis and gluconeogenesis and the current treatments for HCC. We believe that a treatment combination of sorafenib with TME improvement and/or anti-Warburg therapies will set the trend of advanced HCC therapy in the future.

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Metformin attenuates hepatoma cell proliferation by decreasing glycolytic flux through the HIF-1α/PFKFB3/PFK1 pathway

Cited by 60 publications

References 41 publications

Matrix Stiffness-Upregulated MicroRNA-17-5p Attenuates the Intervention Effects of Metformin on HCC Invasion and Metastasis by Targeting the PTEN/PI3K/Akt Pathway

Matrix Stiffness-Upregulated MicroRNA-17-5p Attenuates the Intervention Effects of Metformin on HCC Invasion and Metastasis by Targeting the PTEN/PI3K/Akt Pathway

Monocarboxylate Transporter 4 Is a Therapeutic Target in Non-small Cell Lung Cancer with Aerobic Glycolysis Preference

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

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