Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity

Abstract Most cancer cells primarily produce their energy through a high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen. Pyruvate dehydrogenase kinase (PDK) 1, an enzyme responsible for aerobic glycolysis via phosphorylating and inactivating pyruvate...

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Autores principales:	Ling Jin, Eun-Yeong Kim, Tae-Wook Chung, Chang Woo Han, So Young Park, Jung Ho Han, Sung-Jin Bae, Jong Rok Lee, Young Woo Kim, Se Bok Jang, Ki-Tae Ha
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d15a50f053bb481fa911ceb41d99105f
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spelling	oai:doaj.org-article:d15a50f053bb481fa911ceb41d99105f2021-12-02T13:58:25ZHemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity10.1038/s41598-020-79019-12045-2322https://doaj.org/article/d15a50f053bb481fa911ceb41d99105f2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79019-1https://doaj.org/toc/2045-2322Abstract Most cancer cells primarily produce their energy through a high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen. Pyruvate dehydrogenase kinase (PDK) 1, an enzyme responsible for aerobic glycolysis via phosphorylating and inactivating pyruvate dehydrogenase (PDH) complex, is commonly overexpressed in tumors and recognized as a therapeutic target in colorectal cancer. Hemistepsin A (HsA) is a sesquiterpene lactone isolated from Hemistepta lyrata Bunge (Compositae). Here, we report that HsA is a PDK1 inhibitor can reduce the growth of colorectal cancer and consequent activation of mitochondrial ROS-dependent apoptotic pathway both in vivo and in vitro. Computational simulation and biochemical assays showed that HsA directly binds to the lipoamide-binding site of PDK1, and subsequently inhibits the interaction of PDK1 with the E2 subunit of PDH complex. As a result of PDK1 inhibition, lactate production was decreased, but oxygen consumption was increased. Mitochondrial ROS levels and mitochondrial damage were also increased. Consistent with these observations, the apoptosis of colorectal cancer cells was promoted by HsA with enhanced activation of caspase-3 and -9. These results suggested that HsA might be a potential candidate for developing a novel anti-cancer drug through suppressing cancer metabolism.Ling JinEun-Yeong KimTae-Wook ChungChang Woo HanSo Young ParkJung Ho HanSung-Jin BaeJong Rok LeeYoung Woo KimSe Bok JangKi-Tae HaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ling Jin Eun-Yeong Kim Tae-Wook Chung Chang Woo Han So Young Park Jung Ho Han Sung-Jin Bae Jong Rok Lee Young Woo Kim Se Bok Jang Ki-Tae Ha Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity
description	Abstract Most cancer cells primarily produce their energy through a high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen. Pyruvate dehydrogenase kinase (PDK) 1, an enzyme responsible for aerobic glycolysis via phosphorylating and inactivating pyruvate dehydrogenase (PDH) complex, is commonly overexpressed in tumors and recognized as a therapeutic target in colorectal cancer. Hemistepsin A (HsA) is a sesquiterpene lactone isolated from Hemistepta lyrata Bunge (Compositae). Here, we report that HsA is a PDK1 inhibitor can reduce the growth of colorectal cancer and consequent activation of mitochondrial ROS-dependent apoptotic pathway both in vivo and in vitro. Computational simulation and biochemical assays showed that HsA directly binds to the lipoamide-binding site of PDK1, and subsequently inhibits the interaction of PDK1 with the E2 subunit of PDH complex. As a result of PDK1 inhibition, lactate production was decreased, but oxygen consumption was increased. Mitochondrial ROS levels and mitochondrial damage were also increased. Consistent with these observations, the apoptosis of colorectal cancer cells was promoted by HsA with enhanced activation of caspase-3 and -9. These results suggested that HsA might be a potential candidate for developing a novel anti-cancer drug through suppressing cancer metabolism.
format	article
author	Ling Jin Eun-Yeong Kim Tae-Wook Chung Chang Woo Han So Young Park Jung Ho Han Sung-Jin Bae Jong Rok Lee Young Woo Kim Se Bok Jang Ki-Tae Ha
author_facet	Ling Jin Eun-Yeong Kim Tae-Wook Chung Chang Woo Han So Young Park Jung Ho Han Sung-Jin Bae Jong Rok Lee Young Woo Kim Se Bok Jang Ki-Tae Ha
author_sort	Ling Jin
title	Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity
title_short	Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity
title_full	Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity
title_fullStr	Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity
title_full_unstemmed	Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity
title_sort	hemistepsin a suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/d15a50f053bb481fa911ceb41d99105f
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Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity

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