Division of Hematology and Oncology, Department of Internal Medicine, Chang Bing Show Chwan Memorial Hospital, Changhua 505, Taiwan, ROC.
Department of Biological Science and Technology, China Medical University, Taichung 406, Taiwan, ROC.
Biomed Pharmacother. 2022 Jan;145:112437. doi: 10.1016/j.biopha.2021.112437. Epub 2021 Dec 2.
Nuclear factor-kappa B (NF-κB), an oncogenic transcription factor, modulates tumor formation and progression by inducing the expression of oncogenes involved in proliferation, survival, angiogenesis, and metastasis. Oral multikinase inhibitors, such as sorafenib, regorafenib, and lenvatinib have been used for the treatment of hepatocellular carcinoma (HCC). Both sorafenib and regorafenib were shown to abolish the NF-κB-mediated progression of HCC. However, the effect of lenvatinib on NF-κB-mediated progression of HCC is ambiguous. Therefore, the primary purpose of the present study was to evaluate the inhibitory effect of lenvatinib and its inhibitory mechanism on the NF-κB-mediated progression of HCC in vitro and in vivo. Here, we used two HCC cell lines to identify the cytotoxicity, apoptosis and metastasis effect of lenvatinib. We also applied a Hep3B-bearing animal model to investigate the therapeutic efficacy of lenvatinib on in vivo model. An NF-κB translocation assay, NF-κB reporter gene assay, a Western blotting assay and immunohistochemistry staining were used to investigate the underlying mechanism by which lenvatinib acts on HCC. In this study, we demonstrated that lenvatinib induced extrinsic/intrinsic apoptosis and suppressed the metastasis of HCC both in vitro and in vivo. Lenvatinib may also suppress NF-κB translocation and activation. We also found both protein kinase C delta (PKC-δ) and p38 mitogen-activated protein kinase (MAPK) inactivation participated in lenvatinib-reduced NF-κB signaling. In conclusion, this study reveals that the suppression of PKC-δ, and the p38 MAPK/NF-κB axis is associated with the lenvatinib-inhibited progression of HCC in vitro and in vivo.
核因子-κB（NF-κB）是一种致癌转录因子，通过诱导参与增殖、存活、血管生成和转移的癌基因的表达来调节肿瘤的形成和进展。口腔多激酶抑制剂，如索拉非尼、regorafenib 和 lenvatinib，已被用于治疗肝细胞癌（HCC）。索拉非尼和regorafenib 均被证明可消除 NF-κB 介导的 HCC 进展。然而，lenvatinib 对 NF-κB 介导的 HCC 进展的影响尚不清楚。因此，本研究的主要目的是评估 lenvatinib 及其在体外和体内对 NF-κB 介导的 HCC 进展的抑制作用及其抑制机制。在这里，我们使用两种 HCC 细胞系来确定 lenvatinib 的细胞毒性、凋亡和转移作用。我们还应用 Hep3B 荷瘤动物模型来研究 lenvatinib 在体内模型中的治疗效果。NF-κB 易位分析、NF-κB 报告基因分析、Western blot 分析和免疫组织化学染色用于研究 lenvatinib 作用于 HCC 的潜在机制。在这项研究中，我们证明 lenvatinib 诱导 HCC 的外在/内在凋亡并抑制其转移，无论是在体外还是在体内。Lenvatinib 还可能抑制 NF-κB 易位和激活。我们还发现蛋白激酶 C 德尔塔（PKC-δ）和丝裂原活化蛋白激酶（MAPK）失活均参与 lenvatinib 减少的 NF-κB 信号转导。总之，这项研究揭示了 PKC-δ 和 p38 MAPK/NF-κB 轴的抑制与 lenvatinib 在体外和体内抑制 HCC 进展有关。
