Tenofovir Hampers the Efficacy of Sorafenib in Prolonging Overall Survival in Hepatocellular Carcinoma

Sorafenib is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). These patients may simultaneously receive anti-hepatitis B treatment if they are viremic. The <i>N-Acetylgalactosaminyltransferase 14</i> (<i>GALNT14</i>) gene can serve as a biomar...

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Autores principales:	Kung-Hao Liang, Sung-Fang Chen, Yu-Hua Lin, Yu-De Chu, Yang-Hsiang Lin, Ming-Wei Lai, Chih-Lang Lin, Chau-Ting Yeh
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	drug-drug interactions glycoproteome targeted therapy entecavir hepatitis B Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/561db4041fd940c886045ef37ad752e0
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spelling	oai:doaj.org-article:561db4041fd940c886045ef37ad752e02021-11-25T16:48:45ZTenofovir Hampers the Efficacy of Sorafenib in Prolonging Overall Survival in Hepatocellular Carcinoma10.3390/biomedicines91115392227-9059https://doaj.org/article/561db4041fd940c886045ef37ad752e02021-10-01T00:00:00Zhttps://www.mdpi.com/2227-9059/9/11/1539https://doaj.org/toc/2227-9059Sorafenib is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). These patients may simultaneously receive anti-hepatitis B treatment if they are viremic. The <i>N-Acetylgalactosaminyltransferase 14</i> (<i>GALNT14</i>) gene can serve as a biomarker to guide HCC treatments. However, the enzyme substrates of its gene product, GalNAc-T14 (a glycosyltransferase), remained uncharacterized. Here, we conducted a glycoproteome-wide search for GalNAc-T14 substrates using lectin affinity chromatography followed by tandem mass spectrometry. Seventeen novel GalNAc-T14 substrates were identified. A connective map analysis showed that an antiviral drug, tenofovir, was the leading medicinal compound to down-regulate the expression of these substrates. In vitro assays showed that HCC cells were resistant to sorafenib if pretreated by tenofovir but not entecavir. Clinical analysis showed that the concomitant use of tenofovir and sorafenib was a previously unrecognized predictive factor for unfavorable overall survival (hazard ratio = 2.060, 95% confidence interval = [1.256, 3.381], <i>p</i> = 0.004) in a cohort of 181 hepatitis-B-related, sorafenib-treated HCC patients (concomitant tenofovir versus entecavir treatment; <i>p</i> = 0.003). In conclusion, by conducting a glycoproteome-wide search for GalNAc-T14 substrates, we unexpectedly found that tenofovir was a major negative regulator of GalNAc-T14 substrates and an unfavorable anti-hepatitis B drug in HCC patients receiving sorafenib.Kung-Hao LiangSung-Fang ChenYu-Hua LinYu-De ChuYang-Hsiang LinMing-Wei LaiChih-Lang LinChau-Ting YehMDPI AGarticledrug-drug interactionsglycoproteometargeted therapyentecavirhepatitis BBiology (General)QH301-705.5ENBiomedicines, Vol 9, Iss 1539, p 1539 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	drug-drug interactions glycoproteome targeted therapy entecavir hepatitis B Biology (General) QH301-705.5
spellingShingle	drug-drug interactions glycoproteome targeted therapy entecavir hepatitis B Biology (General) QH301-705.5 Kung-Hao Liang Sung-Fang Chen Yu-Hua Lin Yu-De Chu Yang-Hsiang Lin Ming-Wei Lai Chih-Lang Lin Chau-Ting Yeh Tenofovir Hampers the Efficacy of Sorafenib in Prolonging Overall Survival in Hepatocellular Carcinoma
description	Sorafenib is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). These patients may simultaneously receive anti-hepatitis B treatment if they are viremic. The <i>N-Acetylgalactosaminyltransferase 14</i> (<i>GALNT14</i>) gene can serve as a biomarker to guide HCC treatments. However, the enzyme substrates of its gene product, GalNAc-T14 (a glycosyltransferase), remained uncharacterized. Here, we conducted a glycoproteome-wide search for GalNAc-T14 substrates using lectin affinity chromatography followed by tandem mass spectrometry. Seventeen novel GalNAc-T14 substrates were identified. A connective map analysis showed that an antiviral drug, tenofovir, was the leading medicinal compound to down-regulate the expression of these substrates. In vitro assays showed that HCC cells were resistant to sorafenib if pretreated by tenofovir but not entecavir. Clinical analysis showed that the concomitant use of tenofovir and sorafenib was a previously unrecognized predictive factor for unfavorable overall survival (hazard ratio = 2.060, 95% confidence interval = [1.256, 3.381], <i>p</i> = 0.004) in a cohort of 181 hepatitis-B-related, sorafenib-treated HCC patients (concomitant tenofovir versus entecavir treatment; <i>p</i> = 0.003). In conclusion, by conducting a glycoproteome-wide search for GalNAc-T14 substrates, we unexpectedly found that tenofovir was a major negative regulator of GalNAc-T14 substrates and an unfavorable anti-hepatitis B drug in HCC patients receiving sorafenib.
format	article
author	Kung-Hao Liang Sung-Fang Chen Yu-Hua Lin Yu-De Chu Yang-Hsiang Lin Ming-Wei Lai Chih-Lang Lin Chau-Ting Yeh
author_facet	Kung-Hao Liang Sung-Fang Chen Yu-Hua Lin Yu-De Chu Yang-Hsiang Lin Ming-Wei Lai Chih-Lang Lin Chau-Ting Yeh
author_sort	Kung-Hao Liang
title	Tenofovir Hampers the Efficacy of Sorafenib in Prolonging Overall Survival in Hepatocellular Carcinoma
title_short	Tenofovir Hampers the Efficacy of Sorafenib in Prolonging Overall Survival in Hepatocellular Carcinoma
title_full	Tenofovir Hampers the Efficacy of Sorafenib in Prolonging Overall Survival in Hepatocellular Carcinoma
title_fullStr	Tenofovir Hampers the Efficacy of Sorafenib in Prolonging Overall Survival in Hepatocellular Carcinoma
title_full_unstemmed	Tenofovir Hampers the Efficacy of Sorafenib in Prolonging Overall Survival in Hepatocellular Carcinoma
title_sort	tenofovir hampers the efficacy of sorafenib in prolonging overall survival in hepatocellular carcinoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/561db4041fd940c886045ef37ad752e0
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Tenofovir Hampers the Efficacy of Sorafenib in Prolonging Overall Survival in Hepatocellular Carcinoma

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