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Therapeutic effects of the PKR inhibitor C16 suppressing tumor proliferation and angiogenesis in hepatocellular carcinoma in vitro and in vivo.

ABSTRACT: The therapeutic effects of C16, which is an inhibitor of RNA-dependent protein kinase (PKR), on growth of hepatocellular carcinoma (HCC) cells and tumor progression in vitro and in vivo were evaluated. Huh7 cells, a human HCC cell line, were used. The effects of C16 on cell viability were evaluated with the MTT assay, and real-time RT-PCR was performed. Huh7 cells were grafted into immunodeficient mice, and the in vivo effects of C16 on tumorigenesis were examined. C16 suppressed proliferation of HCC cells in a dose-dependent manner in vitro. Mouse models with xenograft transplantation showed that the inhibitor suppressed the growth of HCC cells in vivo. Moreover, C16 decreased angiogenesis in HCC tissue in the xenograft model. Consistent with these results in mice, transcript levels of vascular endothelial growth factor-A and factor-B, platelet-derived growth factor-A and factor-B, fibroblast growth factor-2, epidermal growth factor, and hepatocyte growth factor, which are angiogenesis-related growth factors, were significantly decreased by C16 in vitro. In conclusion, the PKR inhibitor C16 blocked tumor cell growth and angiogenesis via a decrease in mRNA levels of several growth factors. C16 may be useful in the treatment of HCC.

SUBMITTER: Watanabe T

PROVIDER: S-EPMC7083831 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Therapeutic effects of the PKR inhibitor C16 suppressing tumor proliferation and angiogenesis in hepatocellular carcinoma in vitro and in vivo.

Watanabe Takao T Ninomiya Hiroko H Saitou Takashi T Takanezawa Sota S Yamamoto Shin S Imai Yusuke Y Yoshida Osamu O Kawakami Ryosuke R Hirooka Masashi M Abe Masanori M Imamura Takeshi T Hiasa Yoichi Y

Scientific reports 20200320 1

The therapeutic effects of C16, which is an inhibitor of RNA-dependent protein kinase (PKR), on growth of hepatocellular carcinoma (HCC) cells and tumor progression in vitro and in vivo were evaluated. Huh7 cells, a human HCC cell line, were used. The effects of C16 on cell viability were evaluated with the MTT assay, and real-time RT-PCR was performed. Huh7 cells were grafted into immunodeficient mice, and the in vivo effects of C16 on tumorigenesis were examined. C16 suppressed proliferation o ...[more]

PMID: 32198380

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Project description:OBJECTIVES:The ability of tumor cells to drive angiogenesis is an important cancer hallmark that positively correlates with metastatic potential and poor prognosis. Therefore, targeting angiogenesis is a rational therapeutic approach and dissecting proangiogenic pathways is important, particularly for malignancies driven by oncogenic KRAS, which are widespread and lack effective targeted therapies. Based on published studies showing that oncogenic RAS promotes angiogenesis by upregulating the proangiogenic NF-?B target genes IL-8 and VEGF, that NF-?B activation by KRAS requires the IKK? kinase, and that targeting IKK? reduces KRAS-induced lung tumor growth in vivo, but has limited effects on cell growth in vitro, we hypothesized that IKK? targeting would reduce lung tumor growth by inhibiting KRAS-induced angiogenesis. MATERIALS AND METHODS:To test this hypothesis, we targeted IKK? in KRAS-mutant lung cancer cell lines either by siRNA-mediated transfection or by treatment with Compound A (CmpdA), a highly specific IKK? inhibitor, and used in vitro and in vivo assays to evaluate angiogenesis. RESULTS AND CONCLUSIONS:Both pharmacological and siRNA-mediated IKK? targeting in lung cells reduced expression and secretion of NF-?B-regulated proangiogenic factors IL-8 and VEGF. Moreover, conditioned media from IKK?-targeted lung cells reduced human umbilical vein endothelial cell (HUVEC) migration, invasion and tube formation in vitro. Furthermore, siRNA-mediated IKK? inhibition reduced xenograft tumor growth and vascularity in vivo. Finally, IKK? inhibition also affects endothelial cell function in a cancer-independent manner, as IKK? inhibition reduced pathological retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Taken together, these results provide a novel mechanistic understanding of how the IKK? pathway affects human lung tumorigenesis, indicating that IKK? promotes KRAS-induced angiogenesis both by cancer cell-intrinsic and cancer cell-independent mechanisms, which strongly suggests IKK? inhibition as a promising antiangiogenic approach to be explored for KRAS-induced lung cancer therapy.

Dataset Information

Therapeutic effects of the PKR inhibitor C16 suppressing tumor proliferation and angiogenesis in hepatocellular carcinoma in vitro and in vivo.

Publications

Therapeutic effects of the PKR inhibitor C16 suppressing tumor proliferation and angiogenesis in hepatocellular carcinoma in vitro and in vivo.

Similar Datasets

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