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The Phenoxyphenol Compound diTFPP Mediates Exogenous C(2)-Ceramide Metabolism, Inducing Cell Apoptosis Accompanied by ROS Formation and Autophagy in Hepatocellular Carcinoma Cells

Hepatocellular carcinoma (HCC) is a severe disease that accounts for 80% of liver cancers. Chemotherapy is the primary therapeutic strategy for patients who cannot be treated with surgery or who have late-stage HCC. C(2)-ceramide is an effective reagent that has been found to inhibit the growth of m...

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Autores principales: Chang, Wen-Tsan, Bow, Yung-Ding, Chen, Yen-Chun, Li, Chia-Yang, Chen, Jeff Yi-Fu, Chu, Yi-Ching, Teng, Yen-Ni, Li, Ruei-Nian, Chiu, Chien-Chih
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998835/
https://www.ncbi.nlm.nih.gov/pubmed/33807856
http://dx.doi.org/10.3390/antiox10030394
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author Chang, Wen-Tsan
Bow, Yung-Ding
Chen, Yen-Chun
Li, Chia-Yang
Chen, Jeff Yi-Fu
Chu, Yi-Ching
Teng, Yen-Ni
Li, Ruei-Nian
Chiu, Chien-Chih
author_facet Chang, Wen-Tsan
Bow, Yung-Ding
Chen, Yen-Chun
Li, Chia-Yang
Chen, Jeff Yi-Fu
Chu, Yi-Ching
Teng, Yen-Ni
Li, Ruei-Nian
Chiu, Chien-Chih
author_sort Chang, Wen-Tsan
collection PubMed
description Hepatocellular carcinoma (HCC) is a severe disease that accounts for 80% of liver cancers. Chemotherapy is the primary therapeutic strategy for patients who cannot be treated with surgery or who have late-stage HCC. C(2)-ceramide is an effective reagent that has been found to inhibit the growth of many cancer types. The metabolism of C(2)-ceramide plays a vital role in the regulation of cell death/cell survival. The phenoxyphenol compound 4-{2,3,5,6-tetrafluoro-4-[2,3,5,6-tetrafluoro-4-(4-hydroxyphenoxy)phenyl]phenoxy}phenol (diTFPP) was found to have a synergistic effect with C(2)-ceramide, resulting in considerable cell death in the HA22T HCC cell line. diTFPP/C(2)-ceramide cotreatment induced a two- to threefold increase in cell death compared to that with C2-ceramide alone and induced pyknosis. Annexin V/7-aminoactinomycin D (7AAD) double staining and Western blotting indicated that apoptosis was involved in diTFPP/C(2)-ceramide cotreatment-mediated cell death. We next analyzed transcriptome alterations in diTFPP/C(2)-ceramide-cotreated HA22T cells with next-generation sequencing (NGS). The data indicated that diTFPP treatment disrupted sphingolipid metabolism, inhibited cell cycle-associated gene expression, and induced autophagy and reactive oxygen species (ROS)-responsive changes in gene expression. Additionally, we assessed the activation of autophagy with acridine orange (AO) staining and observed alterations in the expression of the autophagic proteins LC3B-II and Beclin-1, which indicated autophagy activation after diTFPP/C(2)-ceramide cotreatment. Elevated levels of ROS were also reported in diTFPP/C(2)-ceramide-treated cells, and the expression of the ROS-associated proteins SOD1, SOD2, and catalase was upregulated after diTFPP/C(2)-ceramide treatment. This study revealed the potential regulatory mechanism of the novel compound diTFPP in sphingolipid metabolism by showing that it disrupts ceramide metabolism and apoptotic sphingolipid accumulation.
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spelling pubmed-79988352021-03-28 The Phenoxyphenol Compound diTFPP Mediates Exogenous C(2)-Ceramide Metabolism, Inducing Cell Apoptosis Accompanied by ROS Formation and Autophagy in Hepatocellular Carcinoma Cells Chang, Wen-Tsan Bow, Yung-Ding Chen, Yen-Chun Li, Chia-Yang Chen, Jeff Yi-Fu Chu, Yi-Ching Teng, Yen-Ni Li, Ruei-Nian Chiu, Chien-Chih Antioxidants (Basel) Article Hepatocellular carcinoma (HCC) is a severe disease that accounts for 80% of liver cancers. Chemotherapy is the primary therapeutic strategy for patients who cannot be treated with surgery or who have late-stage HCC. C(2)-ceramide is an effective reagent that has been found to inhibit the growth of many cancer types. The metabolism of C(2)-ceramide plays a vital role in the regulation of cell death/cell survival. The phenoxyphenol compound 4-{2,3,5,6-tetrafluoro-4-[2,3,5,6-tetrafluoro-4-(4-hydroxyphenoxy)phenyl]phenoxy}phenol (diTFPP) was found to have a synergistic effect with C(2)-ceramide, resulting in considerable cell death in the HA22T HCC cell line. diTFPP/C(2)-ceramide cotreatment induced a two- to threefold increase in cell death compared to that with C2-ceramide alone and induced pyknosis. Annexin V/7-aminoactinomycin D (7AAD) double staining and Western blotting indicated that apoptosis was involved in diTFPP/C(2)-ceramide cotreatment-mediated cell death. We next analyzed transcriptome alterations in diTFPP/C(2)-ceramide-cotreated HA22T cells with next-generation sequencing (NGS). The data indicated that diTFPP treatment disrupted sphingolipid metabolism, inhibited cell cycle-associated gene expression, and induced autophagy and reactive oxygen species (ROS)-responsive changes in gene expression. Additionally, we assessed the activation of autophagy with acridine orange (AO) staining and observed alterations in the expression of the autophagic proteins LC3B-II and Beclin-1, which indicated autophagy activation after diTFPP/C(2)-ceramide cotreatment. Elevated levels of ROS were also reported in diTFPP/C(2)-ceramide-treated cells, and the expression of the ROS-associated proteins SOD1, SOD2, and catalase was upregulated after diTFPP/C(2)-ceramide treatment. This study revealed the potential regulatory mechanism of the novel compound diTFPP in sphingolipid metabolism by showing that it disrupts ceramide metabolism and apoptotic sphingolipid accumulation. MDPI 2021-03-05 /pmc/articles/PMC7998835/ /pubmed/33807856 http://dx.doi.org/10.3390/antiox10030394 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Chang, Wen-Tsan
Bow, Yung-Ding
Chen, Yen-Chun
Li, Chia-Yang
Chen, Jeff Yi-Fu
Chu, Yi-Ching
Teng, Yen-Ni
Li, Ruei-Nian
Chiu, Chien-Chih
The Phenoxyphenol Compound diTFPP Mediates Exogenous C(2)-Ceramide Metabolism, Inducing Cell Apoptosis Accompanied by ROS Formation and Autophagy in Hepatocellular Carcinoma Cells
title The Phenoxyphenol Compound diTFPP Mediates Exogenous C(2)-Ceramide Metabolism, Inducing Cell Apoptosis Accompanied by ROS Formation and Autophagy in Hepatocellular Carcinoma Cells
title_full The Phenoxyphenol Compound diTFPP Mediates Exogenous C(2)-Ceramide Metabolism, Inducing Cell Apoptosis Accompanied by ROS Formation and Autophagy in Hepatocellular Carcinoma Cells
title_fullStr The Phenoxyphenol Compound diTFPP Mediates Exogenous C(2)-Ceramide Metabolism, Inducing Cell Apoptosis Accompanied by ROS Formation and Autophagy in Hepatocellular Carcinoma Cells
title_full_unstemmed The Phenoxyphenol Compound diTFPP Mediates Exogenous C(2)-Ceramide Metabolism, Inducing Cell Apoptosis Accompanied by ROS Formation and Autophagy in Hepatocellular Carcinoma Cells
title_short The Phenoxyphenol Compound diTFPP Mediates Exogenous C(2)-Ceramide Metabolism, Inducing Cell Apoptosis Accompanied by ROS Formation and Autophagy in Hepatocellular Carcinoma Cells
title_sort phenoxyphenol compound ditfpp mediates exogenous c(2)-ceramide metabolism, inducing cell apoptosis accompanied by ros formation and autophagy in hepatocellular carcinoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998835/
https://www.ncbi.nlm.nih.gov/pubmed/33807856
http://dx.doi.org/10.3390/antiox10030394
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