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Hemistepsin a Induces Apoptosis of Hepatocellular Carcinoma Cells by Downregulating STAT3

Hemistepta lyrata (Bunge) Bunge is a biennial medicinal plant possessing beneficial effects including anti-inflammation, and hemistepsin A (HsA) isolated from H. lyrata has been known as a hepatoprotective sesquiterpene lactone. In this report, we explored the cytotoxic effects of H. lyrata on hepat...

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Autores principales: Cho, Il Je, Kim, Jae Kwang, Kim, Eun Ok, Park, Sang Mi, Kim, Sang Chan, Ki, Sung Hwan, Ku, Sae Kwang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125382/
https://www.ncbi.nlm.nih.gov/pubmed/33947048
http://dx.doi.org/10.3390/ijms22094743
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author Cho, Il Je
Kim, Jae Kwang
Kim, Eun Ok
Park, Sang Mi
Kim, Sang Chan
Ki, Sung Hwan
Ku, Sae Kwang
author_facet Cho, Il Je
Kim, Jae Kwang
Kim, Eun Ok
Park, Sang Mi
Kim, Sang Chan
Ki, Sung Hwan
Ku, Sae Kwang
author_sort Cho, Il Je
collection PubMed
description Hemistepta lyrata (Bunge) Bunge is a biennial medicinal plant possessing beneficial effects including anti-inflammation, and hemistepsin A (HsA) isolated from H. lyrata has been known as a hepatoprotective sesquiterpene lactone. In this report, we explored the cytotoxic effects of H. lyrata on hepatocellular carcinoma (HCC) cells and investigated the associated bioactive compounds and their relevant mechanisms. From the viability results of HCC cells treated with various H. lyrata extracts, HsA was identified as the major compound contributing to the H. lyrata-mediated cytotoxicity. HsA increased expression of cleaved PARP and cells with Sub-G1 phase, Annexin V binding, and TUNEL staining, which imply HsA induces apoptosis. In addition, HsA provoked oxidative stress by decreasing the reduced glutathione/oxidized glutathione ratio and accumulating reactive oxygen species and glutathione-protein adducts. Moreover, HsA inhibited the transactivation of signal transducer and activator of transcription 3 (STAT3) by its dephosphorylation at Y705 and glutathione conjugation. Stable expression of a constitutive active mutant of STAT3 prevented the reduction of cell viability by HsA. Finally, HsA enhanced the sensitivity of sorafenib-mediated cytotoxicity by exaggerating oxidative stress and Y705 dephosphorylation of STAT3. Therefore, HsA will be a promising candidate to induce apoptosis of HCC cells via downregulating STAT3 and sensitizing conventional chemotherapeutic agents.
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spelling pubmed-81253822021-05-17 Hemistepsin a Induces Apoptosis of Hepatocellular Carcinoma Cells by Downregulating STAT3 Cho, Il Je Kim, Jae Kwang Kim, Eun Ok Park, Sang Mi Kim, Sang Chan Ki, Sung Hwan Ku, Sae Kwang Int J Mol Sci Article Hemistepta lyrata (Bunge) Bunge is a biennial medicinal plant possessing beneficial effects including anti-inflammation, and hemistepsin A (HsA) isolated from H. lyrata has been known as a hepatoprotective sesquiterpene lactone. In this report, we explored the cytotoxic effects of H. lyrata on hepatocellular carcinoma (HCC) cells and investigated the associated bioactive compounds and their relevant mechanisms. From the viability results of HCC cells treated with various H. lyrata extracts, HsA was identified as the major compound contributing to the H. lyrata-mediated cytotoxicity. HsA increased expression of cleaved PARP and cells with Sub-G1 phase, Annexin V binding, and TUNEL staining, which imply HsA induces apoptosis. In addition, HsA provoked oxidative stress by decreasing the reduced glutathione/oxidized glutathione ratio and accumulating reactive oxygen species and glutathione-protein adducts. Moreover, HsA inhibited the transactivation of signal transducer and activator of transcription 3 (STAT3) by its dephosphorylation at Y705 and glutathione conjugation. Stable expression of a constitutive active mutant of STAT3 prevented the reduction of cell viability by HsA. Finally, HsA enhanced the sensitivity of sorafenib-mediated cytotoxicity by exaggerating oxidative stress and Y705 dephosphorylation of STAT3. Therefore, HsA will be a promising candidate to induce apoptosis of HCC cells via downregulating STAT3 and sensitizing conventional chemotherapeutic agents. MDPI 2021-04-29 /pmc/articles/PMC8125382/ /pubmed/33947048 http://dx.doi.org/10.3390/ijms22094743 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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cho, Il Je
Kim, Jae Kwang
Kim, Eun Ok
Park, Sang Mi
Kim, Sang Chan
Ki, Sung Hwan
Ku, Sae Kwang
Hemistepsin a Induces Apoptosis of Hepatocellular Carcinoma Cells by Downregulating STAT3
title Hemistepsin a Induces Apoptosis of Hepatocellular Carcinoma Cells by Downregulating STAT3
title_full Hemistepsin a Induces Apoptosis of Hepatocellular Carcinoma Cells by Downregulating STAT3
title_fullStr Hemistepsin a Induces Apoptosis of Hepatocellular Carcinoma Cells by Downregulating STAT3
title_full_unstemmed Hemistepsin a Induces Apoptosis of Hepatocellular Carcinoma Cells by Downregulating STAT3
title_short Hemistepsin a Induces Apoptosis of Hepatocellular Carcinoma Cells by Downregulating STAT3
title_sort hemistepsin a induces apoptosis of hepatocellular carcinoma cells by downregulating stat3
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125382/
https://www.ncbi.nlm.nih.gov/pubmed/33947048
http://dx.doi.org/10.3390/ijms22094743
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