Revealing the suppressive role of protein kinase C delta and p38 mitogen-activated protein kinase (MAPK)/NF-κB axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo

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 bee...

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Autores principales:	Ching-Hsuan Wu, Fei-Ting Hsu, Tsu-Lan Chao, Yuan-Hao Lee, Yu-Cheng Kuo
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Lenvatinib Hepatocellular carcinoma NF-ĸB p38 MAPK PKC-δ Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/23c6c3bfdf354e649f144011c23f16be
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spelling	oai:doaj.org-article:23c6c3bfdf354e649f144011c23f16be2021-12-04T04:33:05ZRevealing the suppressive role of protein kinase C delta and p38 mitogen-activated protein kinase (MAPK)/NF-κB axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo0753-332210.1016/j.biopha.2021.112437https://doaj.org/article/23c6c3bfdf354e649f144011c23f16be2022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221012233https://doaj.org/toc/0753-3322Nuclear 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.Ching-Hsuan WuFei-Ting HsuTsu-Lan ChaoYuan-Hao LeeYu-Cheng KuoElsevierarticleLenvatinibHepatocellular carcinomaNF-ĸBp38 MAPKPKC-δTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112437- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Lenvatinib Hepatocellular carcinoma NF-ĸB p38 MAPK PKC-δ Therapeutics. Pharmacology RM1-950
spellingShingle	Lenvatinib Hepatocellular carcinoma NF-ĸB p38 MAPK PKC-δ Therapeutics. Pharmacology RM1-950 Ching-Hsuan Wu Fei-Ting Hsu Tsu-Lan Chao Yuan-Hao Lee Yu-Cheng Kuo Revealing the suppressive role of protein kinase C delta and p38 mitogen-activated protein kinase (MAPK)/NF-κB axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo
description	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.
format	article
author	Ching-Hsuan Wu Fei-Ting Hsu Tsu-Lan Chao Yuan-Hao Lee Yu-Cheng Kuo
author_facet	Ching-Hsuan Wu Fei-Ting Hsu Tsu-Lan Chao Yuan-Hao Lee Yu-Cheng Kuo
author_sort	Ching-Hsuan Wu
title	Revealing the suppressive role of protein kinase C delta and p38 mitogen-activated protein kinase (MAPK)/NF-κB axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo
title_short	Revealing the suppressive role of protein kinase C delta and p38 mitogen-activated protein kinase (MAPK)/NF-κB axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo
title_full	Revealing the suppressive role of protein kinase C delta and p38 mitogen-activated protein kinase (MAPK)/NF-κB axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo
title_fullStr	Revealing the suppressive role of protein kinase C delta and p38 mitogen-activated protein kinase (MAPK)/NF-κB axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo
title_full_unstemmed	Revealing the suppressive role of protein kinase C delta and p38 mitogen-activated protein kinase (MAPK)/NF-κB axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo
title_sort	revealing the suppressive role of protein kinase c delta and p38 mitogen-activated protein kinase (mapk)/nf-κb axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/23c6c3bfdf354e649f144011c23f16be
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Revealing the suppressive role of protein kinase C delta and p38 mitogen-activated protein kinase (MAPK)/NF-κB axis associates with lenvatinib-inhibited progression in hepatocellular carcinoma in vitro and in vivo

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