Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer Cells
Colorectal cancer (CRC) is the third most common cancer worldwide and is associated with a poor clinical outcome and survival. Therefore, the development of novel therapeutic agents for CRC is imperative. Atractylenolide I (AT-I) is a sesquiterpenoid lactone derivative of Rhizoma Atractylodis macroc...
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doaj-78a37c9c532c489d83523e737739fdf42020-11-25T02:04:50ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-03-011110.3389/fphar.2020.00273502065Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer CellsYanxi Li0Yongpeng Wang1Zhexian Liu2Xingqi Guo3Ziwei Miao4Siping Ma5Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, ChinaDepartment of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, ChinaDepartment of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, ChinaDepartment of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, ChinaDepartment of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, ChinaDepartment of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, ChinaColorectal cancer (CRC) is the third most common cancer worldwide and is associated with a poor clinical outcome and survival. Therefore, the development of novel therapeutic agents for CRC is imperative. Atractylenolide I (AT-I) is a sesquiterpenoid lactone derivative of Rhizoma Atractylodis macrocephalae that exhibits diverse biological activities, including anti-cancer activities. However, the effects and potential mechanism of AT-I in CRC have yet to be fully elucidated. In this study, we aimed to examine the anti-cancer properties of AT-I and the associated functional mechanisms in vitro and in vivo. We found that AT-I treatment significantly suppressed the viability of CRC cell lines and inhibited colony formation, but to a lesser extent in NCM460 cells. Annexin V/PI staining showed that AT-I induced apoptosis in CRC cells, accompanied by increased caspase-3 and PARP-1 cleavage, enhanced expression of Bax, and reduced expression of Bcl-2. Furthermore, AT-I blocked cell glycolysis by inhibiting both glucose uptake and lactate production in CRC cells, and specifically downregulated the expression of the rate-limiting glycolytic enzyme HK2. In contrast, it had no discernable effects on the glycolytic enzymes PFK and PKM2. A mechanistic study revealed that AT-1 negatively regulates STAT3 phosphorylation through direct interaction with JAK2, thereby inhibiting its activation. Moreover, restoring the expression of STAT3 reversed the effect of AT-I on apoptosis and glycolysis in CRC cells. In vivo results revealed that AT-I significantly suppressed tumor growth in HCT116-xenografted mice. Collectively, our findings indicate that the anti-cancer activity of AT-I in CRC is associated with the induction of apoptosis and suppression of glycolysis in CRC cells, via the disruption of JAK2/STAT3 signaling. Our preliminary experimental data indicate that AT-I may have applications as a promising candidate for the treatment of CRC.https://www.frontiersin.org/article/10.3389/fphar.2020.00273/fullatractylenolide Icolorectal cancerapoptosisglycolysisJAK2STAT3 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yanxi Li Yongpeng Wang Zhexian Liu Xingqi Guo Ziwei Miao Siping Ma |
spellingShingle |
Yanxi Li Yongpeng Wang Zhexian Liu Xingqi Guo Ziwei Miao Siping Ma Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer Cells Frontiers in Pharmacology atractylenolide I colorectal cancer apoptosis glycolysis JAK2 STAT3 |
author_facet |
Yanxi Li Yongpeng Wang Zhexian Liu Xingqi Guo Ziwei Miao Siping Ma |
author_sort |
Yanxi Li |
title |
Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer Cells |
title_short |
Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer Cells |
title_full |
Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer Cells |
title_fullStr |
Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer Cells |
title_full_unstemmed |
Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer Cells |
title_sort |
atractylenolide i induces apoptosis and suppresses glycolysis by blocking the jak2/stat3 signaling pathway in colorectal cancer cells |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2020-03-01 |
description |
Colorectal cancer (CRC) is the third most common cancer worldwide and is associated with a poor clinical outcome and survival. Therefore, the development of novel therapeutic agents for CRC is imperative. Atractylenolide I (AT-I) is a sesquiterpenoid lactone derivative of Rhizoma Atractylodis macrocephalae that exhibits diverse biological activities, including anti-cancer activities. However, the effects and potential mechanism of AT-I in CRC have yet to be fully elucidated. In this study, we aimed to examine the anti-cancer properties of AT-I and the associated functional mechanisms in vitro and in vivo. We found that AT-I treatment significantly suppressed the viability of CRC cell lines and inhibited colony formation, but to a lesser extent in NCM460 cells. Annexin V/PI staining showed that AT-I induced apoptosis in CRC cells, accompanied by increased caspase-3 and PARP-1 cleavage, enhanced expression of Bax, and reduced expression of Bcl-2. Furthermore, AT-I blocked cell glycolysis by inhibiting both glucose uptake and lactate production in CRC cells, and specifically downregulated the expression of the rate-limiting glycolytic enzyme HK2. In contrast, it had no discernable effects on the glycolytic enzymes PFK and PKM2. A mechanistic study revealed that AT-1 negatively regulates STAT3 phosphorylation through direct interaction with JAK2, thereby inhibiting its activation. Moreover, restoring the expression of STAT3 reversed the effect of AT-I on apoptosis and glycolysis in CRC cells. In vivo results revealed that AT-I significantly suppressed tumor growth in HCT116-xenografted mice. Collectively, our findings indicate that the anti-cancer activity of AT-I in CRC is associated with the induction of apoptosis and suppression of glycolysis in CRC cells, via the disruption of JAK2/STAT3 signaling. Our preliminary experimental data indicate that AT-I may have applications as a promising candidate for the treatment of CRC. |
topic |
atractylenolide I colorectal cancer apoptosis glycolysis JAK2 STAT3 |
url |
https://www.frontiersin.org/article/10.3389/fphar.2020.00273/full |
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