Overexpression of von Hippel-Lindau protein synergizes with doxorubicin to suppress hepatocellular carcinoma in mice

Jizhou Wang, Yong Ma, Hongchi Jiang, Huaqiang Zhu, Lianxin Liu, Bei Sun, Shangha Pan, Geoffrey W Krissansen, Xueying Sun
Journal of Hepatology 2011, 55 (2): 359-68

BACKGROUND & AIMS: Hypoxia-inducible factors (HIFs) and nuclear factor-κB (NF-κB) regulate genes involved in carcinogenesis and progression of cancers including hepatocellular carcinoma (HCC). The von Hippel-Lindau (VHL) protein (pVHL) targets HIFα subunits for destruction and participates in modulating the activity of NF-κB. The present study aimed to investigate whether the overexpression of pVHL synergizes with doxorubicin in the treatment of HCC.

METHODS: Overexpression of pVHL was induced by infecting mouse HCC Hepa1-6 and H22 cells, or injecting subcutaneous Hepa1-6 tumors in C57BL/c mice, with adenoviral vectors encoding mouse VHL gene. Cell proliferation, apoptosis, tumoral angiogenesis, and gene expression and DNA-binding activity of NF-κB were examined. The therapeutic effects of pVHL were also evaluated in orthotopic Hepa1-6 tumors by intraportal delivery of Ad-VHL.

RESULTS: Ad-VHL enhanced the anti-tumor activity of doxorubicin by inhibiting cell proliferation, and causing cell cycle arrest and apoptosis. The Ad-VHL infection downregulated HIF-1α and HIF-2α expression, and inhibited NF-κB activity and the expression of genes involved in apoptosis, proliferation, angiogenesis, invasion, and metastasis. Injection of Ad-VHL into HCC tumors augmented doxorubicin-induced suppression of tumor growth by inhibiting cell proliferation and tumor angiogenesis, and by inducing cell apoptosis. Effects on the expression of HIFαs, activity of NF-κB, and their downstream genes were in accordance with the in vitro findings. Intraportal injection of Ad-VHL enhanced the efficacy of doxorubicin to suppress the growth of orthotopic liver tumors.

CONCLUSIONS: By targeting HIF and NF-κB, overexpression of pVHL enhances the efficacy of doxorubicin, and warrants consideration as a potential therapeutic strategy for treating HCC.

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