Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade

Ursolic acid (UA), a pentacyclic triterpenoid extracted from various plants, inhibits cell growth, metastasis, and tumorigenesis in various cancers. Chemotherapy resistance and the side effects of paclitaxel (PTX), a traditional chemotherapy reagent, have limited the curative effect of PTX in esopha...

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Autores principales:	Ruo Yu Meng, Hua Jin, Thi Van Nguyen, Ok-Hee Chai, Byung-Hyun Park, Soo Mi Kim
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ursolic acid esophageal squamous cell carcinoma apoptosis FOXM1 Akt Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/d28bd70cecc64f66bf6cb2ef10fc4235
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spelling	oai:doaj.org-article:d28bd70cecc64f66bf6cb2ef10fc42352021-11-11T16:56:57ZUrsolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade10.3390/ijms2221114861422-00671661-6596https://doaj.org/article/d28bd70cecc64f66bf6cb2ef10fc42352021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11486https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Ursolic acid (UA), a pentacyclic triterpenoid extracted from various plants, inhibits cell growth, metastasis, and tumorigenesis in various cancers. Chemotherapy resistance and the side effects of paclitaxel (PTX), a traditional chemotherapy reagent, have limited the curative effect of PTX in esophageal cancer. In this study, we investigate whether UA promotes the anti-tumor effect of PTX and explore the underlying mechanism of their combined effect in esophageal squamous cell carcinoma (ESCC). Combination treatment with UA and PTX inhibited cell proliferation and cell growth more effectively than either treatment alone by inducing more significant apoptosis, as indicated by increased sub-G1 phase distribution and protein levels of cleaved-PARP and cleaved caspase-9. Similar to the cell growth suppressive effect, the combination of UA and PTX significantly inhibited cell migration by targeting uPA, MMP-9, and E-cadherin in ESCC cells. In addition, combination treatment with UA and PTX significantly activated p-GSK-3β and suppressed the activation of Akt and FOXM1 in ESCC cells. Those effects were enhanced by the Akt inhibitor LY2940002 and inverted by the Akt agonist SC79. In an in vivo evaluation of a murine xenograft model of esophageal cancer, combination treatment with UA and PTX suppressed tumor growth significantly better than UA or PTX treatment alone. Thus, UA effectively potentiates the anti-tumor efficacy of PTX by targeting the Akt/FOXM1 cascade since combination treatment shows significantly more anti-tumor potential than PTX alone both in vitro and in vivo. Combination treatment with UA and PTX could be a new strategy for curing esophageal cancer patients.Ruo Yu MengHua JinThi Van NguyenOk-Hee ChaiByung-Hyun ParkSoo Mi KimMDPI AGarticleursolic acidesophageal squamous cell carcinomaapoptosisFOXM1AktBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11486, p 11486 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ursolic acid esophageal squamous cell carcinoma apoptosis FOXM1 Akt Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	ursolic acid esophageal squamous cell carcinoma apoptosis FOXM1 Akt Biology (General) QH301-705.5 Chemistry QD1-999 Ruo Yu Meng Hua Jin Thi Van Nguyen Ok-Hee Chai Byung-Hyun Park Soo Mi Kim Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade
description	Ursolic acid (UA), a pentacyclic triterpenoid extracted from various plants, inhibits cell growth, metastasis, and tumorigenesis in various cancers. Chemotherapy resistance and the side effects of paclitaxel (PTX), a traditional chemotherapy reagent, have limited the curative effect of PTX in esophageal cancer. In this study, we investigate whether UA promotes the anti-tumor effect of PTX and explore the underlying mechanism of their combined effect in esophageal squamous cell carcinoma (ESCC). Combination treatment with UA and PTX inhibited cell proliferation and cell growth more effectively than either treatment alone by inducing more significant apoptosis, as indicated by increased sub-G1 phase distribution and protein levels of cleaved-PARP and cleaved caspase-9. Similar to the cell growth suppressive effect, the combination of UA and PTX significantly inhibited cell migration by targeting uPA, MMP-9, and E-cadherin in ESCC cells. In addition, combination treatment with UA and PTX significantly activated p-GSK-3β and suppressed the activation of Akt and FOXM1 in ESCC cells. Those effects were enhanced by the Akt inhibitor LY2940002 and inverted by the Akt agonist SC79. In an in vivo evaluation of a murine xenograft model of esophageal cancer, combination treatment with UA and PTX suppressed tumor growth significantly better than UA or PTX treatment alone. Thus, UA effectively potentiates the anti-tumor efficacy of PTX by targeting the Akt/FOXM1 cascade since combination treatment shows significantly more anti-tumor potential than PTX alone both in vitro and in vivo. Combination treatment with UA and PTX could be a new strategy for curing esophageal cancer patients.
format	article
author	Ruo Yu Meng Hua Jin Thi Van Nguyen Ok-Hee Chai Byung-Hyun Park Soo Mi Kim
author_facet	Ruo Yu Meng Hua Jin Thi Van Nguyen Ok-Hee Chai Byung-Hyun Park Soo Mi Kim
author_sort	Ruo Yu Meng
title	Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade
title_short	Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade
title_full	Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade
title_fullStr	Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade
title_full_unstemmed	Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade
title_sort	ursolic acid accelerates paclitaxel-induced cell death in esophageal cancer cells by suppressing akt/foxm1 signaling cascade
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d28bd70cecc64f66bf6cb2ef10fc4235
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Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade

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