JI017, a Complex Herbal Medication, Induces Apoptosis via the Nox4–PERK–CHOP Axis in Ovarian Cancer Cells

Many anti-cancer drugs, including paclitaxel and etoposide, have originated and been developed from natural products, and traditional herbal medicines have fewer adverse effects and lesser toxicity than anti-tumor reagents. Therefore, we developed a novel complex herbal medicine, JI017, which mediat...

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Autores principales:	Taewoo Kim, Seong-Gyu Ko
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	JI017 ER stress ROS Nox4 exosome Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/c572a0cda24a442cbd6f1bfb7167881a
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spelling	oai:doaj.org-article:c572a0cda24a442cbd6f1bfb7167881a2021-11-25T17:54:47ZJI017, a Complex Herbal Medication, Induces Apoptosis via the Nox4–PERK–CHOP Axis in Ovarian Cancer Cells10.3390/ijms2222122641422-00671661-6596https://doaj.org/article/c572a0cda24a442cbd6f1bfb7167881a2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12264https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Many anti-cancer drugs, including paclitaxel and etoposide, have originated and been developed from natural products, and traditional herbal medicines have fewer adverse effects and lesser toxicity than anti-tumor reagents. Therefore, we developed a novel complex herbal medicine, JI017, which mediates endoplasmic reticulum (ER) stress and apoptosis through the Nox4–PERK–CHOP signaling pathway in ovarian cancer cells. JI017 treatment increases the expression of GRP78, ATF4, and CHOP and the phosphorylation of PERK and eIF2α via the upregulation of Nox4. Furthermore, it increases the release of intracellular reactive oxygen species (ROS), the production of intracellular Ca<sup>2+</sup>, and the activation of exosomal GRP78 and cell lysate GRP78. Combination treatment using the sarco/endoplasmic reticulum Ca<sup>2+</sup>-ATPase inhibitor thapsigargin (TG) and JI017 reportedly induces increased ER stress and cell death in comparison to the control; however, knockdown experiments of PERK and CHOP indicated suppressed apoptosis and ER stress in JI017-treated ovarian cancer cells. Furthermore, targeting Nox4 using specific siRNA and pharmacological ROS inhibitors, including N-acetylcystein and diphenylene iodonium, blocked apoptosis and ER stress in JI017-treated ovarian cancer cells. In the radioresistant ovarian cancer model, when compared to JI017 alone, JI017 co-treatment with radiation induced greater cell death and resulted in overcoming radioresistance by inhibiting epithelial–mesenchymal-transition-related phenomena such as the reduction of E-cadherin and the increase of N-cadherin, vimentin, Slug, and Snail. These findings suggest that JI017 is a powerful anti-cancer drug for ovarian cancer treatment and that its combination treatment with radiation may be a novel therapeutic strategy for radioresistant ovarian cancer.Taewoo KimSeong-Gyu KoMDPI AGarticleJI017ER stressROSNox4exosomeBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12264, p 12264 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	JI017 ER stress ROS Nox4 exosome Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	JI017 ER stress ROS Nox4 exosome Biology (General) QH301-705.5 Chemistry QD1-999 Taewoo Kim Seong-Gyu Ko JI017, a Complex Herbal Medication, Induces Apoptosis via the Nox4–PERK–CHOP Axis in Ovarian Cancer Cells
description	Many anti-cancer drugs, including paclitaxel and etoposide, have originated and been developed from natural products, and traditional herbal medicines have fewer adverse effects and lesser toxicity than anti-tumor reagents. Therefore, we developed a novel complex herbal medicine, JI017, which mediates endoplasmic reticulum (ER) stress and apoptosis through the Nox4–PERK–CHOP signaling pathway in ovarian cancer cells. JI017 treatment increases the expression of GRP78, ATF4, and CHOP and the phosphorylation of PERK and eIF2α via the upregulation of Nox4. Furthermore, it increases the release of intracellular reactive oxygen species (ROS), the production of intracellular Ca<sup>2+</sup>, and the activation of exosomal GRP78 and cell lysate GRP78. Combination treatment using the sarco/endoplasmic reticulum Ca<sup>2+</sup>-ATPase inhibitor thapsigargin (TG) and JI017 reportedly induces increased ER stress and cell death in comparison to the control; however, knockdown experiments of PERK and CHOP indicated suppressed apoptosis and ER stress in JI017-treated ovarian cancer cells. Furthermore, targeting Nox4 using specific siRNA and pharmacological ROS inhibitors, including N-acetylcystein and diphenylene iodonium, blocked apoptosis and ER stress in JI017-treated ovarian cancer cells. In the radioresistant ovarian cancer model, when compared to JI017 alone, JI017 co-treatment with radiation induced greater cell death and resulted in overcoming radioresistance by inhibiting epithelial–mesenchymal-transition-related phenomena such as the reduction of E-cadherin and the increase of N-cadherin, vimentin, Slug, and Snail. These findings suggest that JI017 is a powerful anti-cancer drug for ovarian cancer treatment and that its combination treatment with radiation may be a novel therapeutic strategy for radioresistant ovarian cancer.
format	article
author	Taewoo Kim Seong-Gyu Ko
author_facet	Taewoo Kim Seong-Gyu Ko
author_sort	Taewoo Kim
title	JI017, a Complex Herbal Medication, Induces Apoptosis via the Nox4–PERK–CHOP Axis in Ovarian Cancer Cells
title_short	JI017, a Complex Herbal Medication, Induces Apoptosis via the Nox4–PERK–CHOP Axis in Ovarian Cancer Cells
title_full	JI017, a Complex Herbal Medication, Induces Apoptosis via the Nox4–PERK–CHOP Axis in Ovarian Cancer Cells
title_fullStr	JI017, a Complex Herbal Medication, Induces Apoptosis via the Nox4–PERK–CHOP Axis in Ovarian Cancer Cells
title_full_unstemmed	JI017, a Complex Herbal Medication, Induces Apoptosis via the Nox4–PERK–CHOP Axis in Ovarian Cancer Cells
title_sort	ji017, a complex herbal medication, induces apoptosis via the nox4–perk–chop axis in ovarian cancer cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c572a0cda24a442cbd6f1bfb7167881a
work_keys_str_mv	AT taewookim ji017acomplexherbalmedicationinducesapoptosisviathenox4perkchopaxisinovariancancercells AT seonggyuko ji017acomplexherbalmedicationinducesapoptosisviathenox4perkchopaxisinovariancancercells
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JI017, a Complex Herbal Medication, Induces Apoptosis via the Nox4–PERK–CHOP Axis in Ovarian Cancer Cells

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