Role of cantharidin in the activation of IKKα/IκBα/NF‑κB pathway by inhibiting PP2A activity in cholangiocarcinoma cell lines

Zhou, Honggeng; Xu, Jiangfeng; Wang, Shuai; Peng, Jinghui

doi:10.3892/mmr.2018.8860

Cited by 10 publications

(7 citation statements)

References 47 publications

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“…Moreover, cantharidin has been shown to increase the level of Bax, inhibit the level of Bcl-2 and survivin expression (Zhang et al, 2005), subsequently resulting in apoptotic cell death (Bonness et al, 2006). Particularly, cantharidin inhibits cancer cell migration and invasion via activating the IKKα/IκBα/NF-κB pathway by inhibiting PP2A activity (Zhou et al, 2018) or suppressing the MMPs (Ji et al, 2015; Shen et al, 2015), suggesting it may be a potential anti-metastatic compound. However, its anti-metastatic mechanism is far less understood.…”

Section: Introductionmentioning

confidence: 99%

Breaking Glucose Transporter 1/Pyruvate Kinase M2 Glycolytic Loop Is Required for Cantharidin Inhibition of Metastasis in Highly Metastatic Breast Cancer

Pan

Zheng

et al. 2019

Front. Pharmacol.

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Aerobic glycolysis plays a decisive role in cancer growth. However, its role in cancer metastasis was rarely understood. Cantharidin a natural compound from an arthropod insect cantharis exerts potent anticancer activity. Here we found cantharidin possesses significant anti-metastatic activity on breast cancer dependent on inhibition of aerobic glycolysis. Cantharidin indicates significant inhibition on migration and invasion of breast cancer cells, angiogenesis in vitro , and inhibits breast cancer cells metastasizing to liver and lung in vivo . Subsequent results revealed that cantharidin decreases the extracellular acidification rates (ECAR) but increases the oxygen consumption rates (OCR) in high metastatic cells, leading to suppression of aerobic glycolysis. This was considered to be due to inhibiting the activity of pyruvate kinase (PK) and further blocking pyruvate kinase M2 (PKM2) translocation in nucleus. Fructose-1,6-bisphosphate (FBP) and L-cysteine can significantly reverse cantharidin inhibition on breast cancer cell migration, invasion, and PKM2 translocation. Furthermore, glucose transporter 1 (GLUT1) forming a metabolic loop with PKM2 is downregulated, as well as epidermal growth factor receptor (EGFR), the regulator of the glycolytic loop. Totally, cantharidin inhibits the PKM2 nuclear translocation and breaks GLUT1/PKM2 glycolytic loop, resulting in aerobic glycolysis transformation to oxidation and subsequent reversing the metastases in breast cancer. Based on inhibiting multi signals mediated aerobic glycolysis, cantharidin could be prospectively used for prevention of metastasis in breast cancer patients.

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Section: Introductionmentioning

confidence: 99%

Breaking Glucose Transporter 1/Pyruvate Kinase M2 Glycolytic Loop Is Required for Cantharidin Inhibition of Metastasis in Highly Metastatic Breast Cancer

Pan

Zheng

et al. 2019

Front. Pharmacol.

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“…Given that p-ERK is the main target of sorafenib and that MLN4924 did not have any effect on p-ERK levels, this suggests that ERK was not involved in MLN4924-mediated sorafinib sensitization. A previous study reported that MMP9, a downstream target of NF-κB, was important for regulating cell migration (30). However, we found that MMP9 was not associated with sorafineb sensitization triggered by MLN4924 in HCC cells, as indicated by no significant changes to MMP9 levels in the presence or absence of MLN4924.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of neddylation modification by MLN4924 sensitizes hepatocellular carcinoma cells to sorafenib

et al. 2019

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Sorafenib remains the standard care for patients with hepatocellular carcinoma (HCC) even though it has low antitumor efficacy. Protein neddylation is abnormally activated in many types of human cancer. However, whether dysregulation of neddylation is involved in HCC progression and whether targeting neddylation sensitizes HCC cells to sorafenib need to be ascertained. In the present study, it was demonstrated that high expression of neddylation components, neural precursor cell expressed, developmentally downregulated 8 (NEDD8) and NEDD8-activating enzyme 1 (NAE1), were associated with poor survival of patients with HCC. Inhibition of neddylation by MLN4924, a small-molecule inhibitor of NAE1, significantly inhibited HCC growth, reduced clonogenic survival, increased apoptosis, and decreased migration capacity. Sorafenib alone exhibited minimal anticancer efficacy. However, a combination of sorafenib with MLN4924 at a low concentration significantly enhanced the inhibition of cell proliferation and migration as well as the induction of apoptosis induced by sorafenib. In vivo HCC xenograft mouse models also showed that MLN4924 increased the antitumor efficacy of sorafenib. Mechanistically, MLN4924 enhanced the antitumor activity of sorafenib in HCC cells via upregulation of cullin-RING E3 ubiquitin ligase (CRL)/Skp1-Cullin1-F box (SCF) E3 ubiquitin ligase substrates p21, p27, Deptor and IκBɑ. Taken together, these findings suggest that combination therapy of MLN4924 with sorafenib appears to present an additive effect with a maximal in the treatment of HCC.

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“…Pathway analysis results demonstrated seven signaling pathways closely related to HCC treatment, involving phenylalanine, tyrosine and tryptophan biosynthesis, d ‐glutamine and d ‐glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine metabolism, arginine biosynthesis, the TCA cycle, and purine metabolism. Among them, cantharidin can affect the expression of related enzymes involved in the TCA cycle by regulating the NF‐ κ B pathway (Todisco et al, 2019; Yang, Zhang, et al, 2021; Zhou et al, 2018). Ginsenosides Rg1 and Rd can block the de novo purine biosynthetic pathway by inhibiting the PI3K/AKT/mTOR pathway (Li et al, 2019; Pedley & Benkovic, 2017; Zhang et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Cell metabolomics study on synergistic anti‐hepatocellular carcinoma effect of Aidi injection combined with doxorubicin

Wang

Zhu

Wang

et al. 2022

Biomedical Chromatography

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Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the second most common cause of cancer deaths. This study aimed to explore the inhibitory effect and mechanism of Aidi injection (ADI) combined with doxorubicin (DOX) in HCC treatment. The drug concentrations in the combined therapy was determined by investigating the effect of various concentrations of ADI and DOX on the viability of H22 cells. The combination index was also calculated. A metabolomic strategy based on a ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) platform was established to analyze the metabolites. As a result, the combination index values were less than 1, indicating that the combination of ADI and DOX exerted a synergistic effect on HCC treatment. The combination of 40‰ ADI and 1 μmol/l DOX had the strongest inhibitory effect and was used for subsequent metabolomic analysis. A total of 19 metabolic markers were obtained in metabolomic analysis, including amino acids (L-glutamic acid, L-arginine and L-tyrosine), organic acids (succinic acid and citric acid), adenosine and hypoxanthine. Compared with the treatment using DOX or ADI alone, the combined therapy further regulated the levels of metabolic markers in HCC, which may be the reason for the synergistic effect. Seven metabolic pathways were significantly enriched, including phenylalanine, tyrosine and tryptophan biosynthesis, D-glutamine and D-glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine metabolism, arginine biosynthesis, the tricarboxylic acid cycle and purine metabolism. These findings demonstrated that ADI combined with DOX can effectively inhibit the viability of H22 cells, which may exert a synergistic antitumor effect by balancing the metabolism of amino acids and energy-related substances.

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Role of cantharidin in the activation of IKKα/IκBα/NF‑κB pathway by inhibiting PP2A activity in cholangiocarcinoma cell lines

Cited by 10 publications

References 47 publications

Breaking Glucose Transporter 1/Pyruvate Kinase M2 Glycolytic Loop Is Required for Cantharidin Inhibition of Metastasis in Highly Metastatic Breast Cancer

Breaking Glucose Transporter 1/Pyruvate Kinase M2 Glycolytic Loop Is Required for Cantharidin Inhibition of Metastasis in Highly Metastatic Breast Cancer

Inhibition of neddylation modification by MLN4924 sensitizes hepatocellular carcinoma cells to sorafenib

Cell metabolomics study on synergistic anti‐hepatocellular carcinoma effect of Aidi injection combined with doxorubicin

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