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The anti-angiogenic effect of dexamethasone in a murine hepatocellular carcinoma model by augmentation of gluconeogenesis pathway in malignant cells

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Abstract

Purpose

Angiogenesis is a long-term complex process involving various protein factors in hepatocellular carcinoma (HCC). Dexamethasone (Dex), considered as a synthetic glucocorticoid drug in clinical therapy, has been reported to have the therapeutic efficacy against liver cancer by intervention of abnormal glycolysis. In this study, we investigated the anti-angiogenic effect of Dex in murine liver cancer and attempted to demonstrate the potential mechanism.

Methods

The malignant cells H22 were treated with Dex. Western blotting was used to explore the expression of PEPCK and G6Pase which were the two key enzymes that regulated gluconeogenesis. The supernatants from cultured H22 treated by Dex were collected and co-cultured with HUVECs. In vitro, migration assay, transwell assay and tube formation assay were performed to assess for migration, proliferation and tube formation abilities of HUVECs, respectively. In situ murine hepatoma model with green fluorescent protein markers (HepG2-GFP) was constructed to determine angiogenesis after treatment by Dex.

Results

PEPCK and G6Pase were almost deficient in H22 compared with normal liver cells NCTC-1469 (P < 0.01). After treated by Dex, the gluconeogenesis could be restored significantly (P < 0.01) in H22 cells. The supernatant of H22 treated by Dex inhibited the migration, tube formation and endothelial permeability in HUVECs (P < 0.05). In mouse tissue, PEPCK and G6Pase were highly expressed in Dex group than control groups (P < 0.01). 11β-HSDs abnormally expressed in tumor also could be restored by Dex. Meanwhile, the density and total length of microvessels in Dex-treated group were less than those in HCC groups (P < 0.05).

Conclusions

This study explored the therapeutic efficacy of Dex in murine HCC. Dex might inhibit tumor growth and angiogenesis by augmenting the gluconeogenesis pathway.

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Acknowledgments

This work was supported by the Postgraduate innovation fund of Peking Union Medical College (No. 2014-10023-1001-017).

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Authors and Affiliations

  1. Key Laboratory for Microcirculation, Ministry of National Health of China Institute of Microcirculation, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), No.5 Dong Dan San Tiao, Dongcheng District, 100005, Beijing, China

    Fei Shang, Mingming Liu, Bingwei Li, Xiaoyan Zhang, Youming Sheng, Shuying Liu, Jianqun Han, Hongwei Li & Ruijuan Xiu

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  1. Fei Shang
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  2. Mingming Liu
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Correspondence to Ruijuan Xiu.

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Shang, F., Liu, M., Li, B. et al. The anti-angiogenic effect of dexamethasone in a murine hepatocellular carcinoma model by augmentation of gluconeogenesis pathway in malignant cells. Cancer Chemother Pharmacol 77, 1087–1096 (2016). https://doi.org/10.1007/s00280-016-3030-x

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