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Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells

Colorectal cancer (CRC) is an aggressive cancer. Isoalantolactone (IATL) has been reported to exert cytotoxicity against various cancer cells, but not CRC. In this study, we explored the anti-CRC effects and mechanism of action of IATL in vitro and in vivo. Our results demonstrated that IATL inhibit...

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Autores principales: Li, Junkui, Zhu, Peili, Chen, Yifei, Zhang, Shiqing, Zhang, Zhu, Zhang, Zhang, Wang, Ying, Jiang, Xiaoli, Lin, Kaili, Wu, Wei, Mo, Zhixian, Sze, Stephen Cho Wing, Yung, Ken Kin Lam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133875/
https://www.ncbi.nlm.nih.gov/pubmed/35645799
http://dx.doi.org/10.3389/fphar.2022.903599
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author Li, Junkui
Zhu, Peili
Chen, Yifei
Zhang, Shiqing
Zhang, Zhu
Zhang, Zhang
Wang, Ying
Jiang, Xiaoli
Lin, Kaili
Wu, Wei
Mo, Zhixian
Sze, Stephen Cho Wing
Yung, Ken Kin Lam
author_facet Li, Junkui
Zhu, Peili
Chen, Yifei
Zhang, Shiqing
Zhang, Zhu
Zhang, Zhang
Wang, Ying
Jiang, Xiaoli
Lin, Kaili
Wu, Wei
Mo, Zhixian
Sze, Stephen Cho Wing
Yung, Ken Kin Lam
author_sort Li, Junkui
collection PubMed
description Colorectal cancer (CRC) is an aggressive cancer. Isoalantolactone (IATL) has been reported to exert cytotoxicity against various cancer cells, but not CRC. In this study, we explored the anti-CRC effects and mechanism of action of IATL in vitro and in vivo. Our results demonstrated that IATL inhibited proliferation by inducing G0/G1 phase cell cycle arrest, apoptosis and autophagy in CRC cells. Repression of autophagy with autophagy inhibitors chloroquine (CQ) and Bafilomycin A1 (Baf-A1) enhanced the anti-CRC effects of IATL, suggesting that IATL induces cytoprotective autophagy in CRC cells. Mechanistic studies revealed that IATL lowered protein levels of phospho-AKT (Ser473), phospho-mTOR (Ser2448), phospho-70S6K (Thr421/Ser424) in CRC cells. Inhibition of AKT and mTOR activities using LY294002 and rapamycin, respectively, potentiated the inductive effects of IATL on autophagy and cell death. In vivo studies showed that IATL suppressed HCT116 tumor growth without affecting the body weight of mice. In consistent with the in vitro results, IATL lowered protein levels of Bcl-2, Bcl-XL, phospho-AKT (Ser473), phospho-mTOR (Ser2448), and phsopho-70S6K (Thr421/Ser424), whereas upregulated protein levels of cleaved-PARP and LC3B-II in HCT116 tumors. Collectively, our results demonstrated that in addition to inhibiting proliferation, inducing G0/G1-phase cell cycle arrest and apoptosis, IATL initiates cytoprotective autophagy in CRC cells by inhibiting the AKT/mTOR signaling pathway. These findings provide an experimental basis for the evaluation of IATL as a novel medication for CRC treatment.
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spelling pubmed-91338752022-05-27 Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells Li, Junkui Zhu, Peili Chen, Yifei Zhang, Shiqing Zhang, Zhu Zhang, Zhang Wang, Ying Jiang, Xiaoli Lin, Kaili Wu, Wei Mo, Zhixian Sze, Stephen Cho Wing Yung, Ken Kin Lam Front Pharmacol Pharmacology Colorectal cancer (CRC) is an aggressive cancer. Isoalantolactone (IATL) has been reported to exert cytotoxicity against various cancer cells, but not CRC. In this study, we explored the anti-CRC effects and mechanism of action of IATL in vitro and in vivo. Our results demonstrated that IATL inhibited proliferation by inducing G0/G1 phase cell cycle arrest, apoptosis and autophagy in CRC cells. Repression of autophagy with autophagy inhibitors chloroquine (CQ) and Bafilomycin A1 (Baf-A1) enhanced the anti-CRC effects of IATL, suggesting that IATL induces cytoprotective autophagy in CRC cells. Mechanistic studies revealed that IATL lowered protein levels of phospho-AKT (Ser473), phospho-mTOR (Ser2448), phospho-70S6K (Thr421/Ser424) in CRC cells. Inhibition of AKT and mTOR activities using LY294002 and rapamycin, respectively, potentiated the inductive effects of IATL on autophagy and cell death. In vivo studies showed that IATL suppressed HCT116 tumor growth without affecting the body weight of mice. In consistent with the in vitro results, IATL lowered protein levels of Bcl-2, Bcl-XL, phospho-AKT (Ser473), phospho-mTOR (Ser2448), and phsopho-70S6K (Thr421/Ser424), whereas upregulated protein levels of cleaved-PARP and LC3B-II in HCT116 tumors. Collectively, our results demonstrated that in addition to inhibiting proliferation, inducing G0/G1-phase cell cycle arrest and apoptosis, IATL initiates cytoprotective autophagy in CRC cells by inhibiting the AKT/mTOR signaling pathway. These findings provide an experimental basis for the evaluation of IATL as a novel medication for CRC treatment. Frontiers Media S.A. 2022-05-12 /pmc/articles/PMC9133875/ /pubmed/35645799 http://dx.doi.org/10.3389/fphar.2022.903599 Text en Copyright © 2022 Li, Zhu, Chen, Zhang, Zhang, Zhang, Wang, Jiang, Lin, Wu, Mo, Sze and Yung. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Li, Junkui
Zhu, Peili
Chen, Yifei
Zhang, Shiqing
Zhang, Zhu
Zhang, Zhang
Wang, Ying
Jiang, Xiaoli
Lin, Kaili
Wu, Wei
Mo, Zhixian
Sze, Stephen Cho Wing
Yung, Ken Kin Lam
Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells
title Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells
title_full Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells
title_fullStr Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells
title_full_unstemmed Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells
title_short Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells
title_sort isoalantolactone induces cell cycle arrest, apoptosis and autophagy in colorectal cancer cells
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133875/
https://www.ncbi.nlm.nih.gov/pubmed/35645799
http://dx.doi.org/10.3389/fphar.2022.903599
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