Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma

Du, Danyu; Liu, Chan; Qin, Mengyao; Zhang, Xiao; Xi, Tao; Yuan, Shengtao; Hao, Haiping; Xiong, Jing

doi:10.1016/j.apsb.2021.09.019

Cited by 295 publications

(209 citation statements)

References 225 publications

(257 reference statements)

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“…It is necessary to fulfill the bioenergetic and biosynthetic demands for tumor growth and adaptation to changing tumor microenvironments [ 15 ]. HCC is also characterized by significant alterations in metabolic processes, ranging from glucose metabolism and energy production to amino acid and fatty acid metabolism [ 16 , 17 ]. It is well known that increased glucose uptake in HCC is related to tumor aggressiveness and poor clinical outcomes [ 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of Exogenous Treatment with Histidine on Hepatocellular Carcinoma Cells

Park

Han

Kim

et al. 2022

Cancers

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib, a multi-kinase inhibitor, is the first-line therapy for advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity and the development of resistance. Although various amino acids have been shown to contribute to cancer initiation and progression, little is known about the effects of histidine, a dietary essential amino acid that is partially taken up via histidine/large neutral amino acid transporter (LAT1), on cancer cells. In this study, we evaluated the effects of histidine on HCC cells and sensitivity to sorafenib. Remarkably, we found that exogenous histidine treatment induced a reduction in the expression of tumor markers related to glycolysis (GLUT1 and HK2), inflammation (STAT3), angiogenesis (VEGFB and VEGFC), and stem cells (CD133). In addition, LAT1 expression was downregulated in HCC tumor regions with high expression of GLUT1, CD133, and pSTAT3, which are known to induce sorafenib resistance. Finally, we demonstrated that combined treatment with sorafenib and histidine could be a novel therapeutic strategy to enhance the sensitivity to sorafenib, thereby improving long-term survival in HCC.

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Section: Introductionmentioning

confidence: 99%

Impact of Exogenous Treatment with Histidine on Hepatocellular Carcinoma Cells

Park

Han

Kim

et al. 2022

Cancers

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“…Therefore, targeting metabolism-related factors or pathways is considered as a promising approach for controlling tumor growth and enhancing the sensitivity of cancer cells to antitumor agents ( Li R. et al, 2021 ; Damaghi et al, 2021 ). The glucose and lipid metabolism pathways have been verified to be closely related, and almost >60% of the carbons in glucose uptake by cells are used to synthesize fatty acids, which mediate energy storage and induce the generation of oncogenic molecules to meet the abundant supply of lipids required for rapid cancerous cell proliferation ( Guo et al, 2014 ; Icard et al, 2020 ; Du et al, 2022 ). SREBP-1 is a transcription factor bound to the sterol regulatory elements (SREs) located in the promoters of its target genes involved in fatty acid and triglyceride synthesis ( Hagen et al, 2010 ; Galbraith et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

A Novel Small-Molecule Inhibitor of SREBP-1 Based on Natural Product Monomers Upregulates the Sensitivity of Lung Squamous Cell Carcinoma Cells to Antitumor Drugs

Liu

Jia

et al. 2022

Front. Pharmacol.

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The transcription factor, sterol regulatory element binding protein 1 (SREBP-1), plays important roles in modulating the proliferation, metastasis, or resistance to antitumor agents by promoting cellular lipid metabolism and related cellular glucose-uptake/Warburg Effect. However, the underlying mechanism of SREBP-1 regulating the proliferation or drug-resistance in lung squamous cell carcinoma (LUSC) and the therapeutic strategies targeted to SREBP-1 in LUSC remain unclear. In this study, SREBP-1 was highly expressed in LUSC tissues, compared with the paired non-tumor tissues (the para-tumor tissues). A novel small-molecule inhibitor of SREBP-1, MSI-1 (Ma’s inhibitor of SREBP-1), based on natural product monomers, was identified by screening the database of natural products. Treatment with MSI-1 suppressed the activation of SREBP-1-related pathways and the Warburg effect of LUSC cells, as indicated by decreased glucose uptake or glycolysis. Moreover, treatment of MSI-1 enhanced the sensitivity of LUSC cells to antitumor agents. The specificity of MSI-1 on SREBP-1 was confirmed by molecular docking and point-mutation of SPEBP-1. Therefore, MSI-1 improved our understanding of SREBP-1 and provided additional options for the treatment of LUSC.

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“… 8 Hence, targeting the enzymes that play a key role in aerobic glycolysis could regulate various phenotypes of the cancer cells and has been regarded as a novel HCC treatment strategy. 40 Preclinical studies have signified that glycolytic inhibitors, such as chrysin (targeting HK2), 41 2‐DG (targeting HK2), 42 , 43 proanthocyanidin B2 (targeting PKM2), 28 methyl jasmonate (targeting HK2) 44 and genistein (targeting HIF‐1α), 45 suppress proliferation and induce apoptosis of the HCC cells. Moreover, these glycolytic inhibitors augment the anti‐HCC effects of sorafenib.…”

Section: Discussionmentioning

confidence: 99%

Sodium butyrate inhibits aerobic glycolysis of hepatocellular carcinoma cells via the c‐myc/hexokinase 2 pathway

Dai

et al. 2022

J Cellular Molecular Medi

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Aerobic glycolysis is a well-known hallmark of hepatocellular carcinoma (HCC). Hence, targeting the key enzymes of this pathway is considered a novel approach to HCC treatment. The effects of sodium butyrate (NaBu), a sodium salt of the short-chain fatty acid butyrate, on aerobic glycolysis in HCC cells and the underlying mechanism are unknown. In the present study, data obtained from cell lines with mouse xenograft model revealed that NaBu inhibited aerobic glycolysis in the HCC cells in vivo and in vitro. NaBu induced apoptosis while inhibiting the proliferation of the HCC cells in vivo and in vitro. Furthermore, the compound inhibited the release of lactate and glucose consumption in the HCC cells in vitro and inhibited the production of lactate in vivo. The modulatory effects of NaBu on glycolysis, proliferation and apoptosis were related to its modulation of hexokinase 2 (HK2). NaBu downregulated HK2 expression via c-myc signalling. The upregulation of glycolysis in the HCC cells induced by sorafenib was impeded by NaBu, thereby enhancing the anti-HCC effect of sorafenib in vitro and in vivo. Thus, NaBu inhibits the expression of HK2 to downregulate aerobic glycolysis and the proliferation of HCC cells and induces their apoptosis via the c-myc pathway.

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Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma

Cited by 295 publications

References 225 publications

Impact of Exogenous Treatment with Histidine on Hepatocellular Carcinoma Cells

Impact of Exogenous Treatment with Histidine on Hepatocellular Carcinoma Cells

A Novel Small-Molecule Inhibitor of SREBP-1 Based on Natural Product Monomers Upregulates the Sensitivity of Lung Squamous Cell Carcinoma Cells to Antitumor Drugs

Sodium butyrate inhibits aerobic glycolysis of hepatocellular carcinoma cells via the c‐myc/hexokinase 2 pathway

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