2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress
Cholesterol metabolism affects endoplasmic reticulum (ER) stress and modulates epithelial-mesenchymal transition (EMT). Our previous study demonstrated that 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) attenuated EMT by blocking the transforming growth factor (TGF)-β/Smad signaling pathway and activatin...
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doaj-7ba6499cc14b4c93ae065f61673863702021-08-26T14:03:58ZengMDPI AGMetabolites2218-19892021-08-011156256210.3390/metabo110805622-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum StressYiyang Zhao0Linkang He1Tian Wang2Lifang Zhu3Nianlong Yan4Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Nanchang University, Nanchang 330006, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medical Science, Nanchang University, Nanchang 330006, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medical Science, Nanchang University, Nanchang 330006, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medical Science, Nanchang University, Nanchang 330006, ChinaDepartment of Biochemistry and Molecular Biology, College of Basic Medical Science, Nanchang University, Nanchang 330006, ChinaCholesterol metabolism affects endoplasmic reticulum (ER) stress and modulates epithelial-mesenchymal transition (EMT). Our previous study demonstrated that 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) attenuated EMT by blocking the transforming growth factor (TGF)-β/Smad signaling pathway and activating ER stress in MDA-MB-231 cells. To further assess the detailed mechanisms between cholesterol metabolism, ER stress, and EMT, LXR-623 (an agonist of LXRα) and simvastatin were used to increase and decrease cholesterol efflux and synthesis, respectively. Here, we found that high HP-β-CD concentrations could locally increase cholesterol levels in the ER by decreasing LXRα expression and increasing Hydroxymethylglutaryl-Coenzyme A reductase (HMGCR) expression in MDA-MB-231 and BT-549 cells, which triggered ER stress and inhibited EMT. Meanwhile, tunicamycin-induced ER stress blocked the TGF-β/Smad signaling pathway. However, low HP-β-CD concentrations can decrease the level of membrane cholesterol, enhance the TGF-β receptor I levels in lipid rafts, which helped to activate TGF-β/Smad signaling pathway, inhibit ER stress and elevate EMT. Based on our findings, the use of high HP-β-CD concentration can lead to cholesterol accumulation in the ER, thereby inducing ER stress, which directly suppresses TGF-β pathway-induced EMT. However, HP-β-CD is proposed to deplete membrane cholesterol at low concentrations and concurrently inhibit ER stress and induce EMT by promoting the TGF-β signaling pathways.https://www.mdpi.com/2218-1989/11/8/5622-hydroxypropyl-β-cyclodextrincholesterol metabolismendoplasmic reticulum stressTGF-β/Smad signaling pathwayepithelial-mesenchymal transition |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yiyang Zhao Linkang He Tian Wang Lifang Zhu Nianlong Yan |
spellingShingle |
Yiyang Zhao Linkang He Tian Wang Lifang Zhu Nianlong Yan 2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress Metabolites 2-hydroxypropyl-β-cyclodextrin cholesterol metabolism endoplasmic reticulum stress TGF-β/Smad signaling pathway epithelial-mesenchymal transition |
author_facet |
Yiyang Zhao Linkang He Tian Wang Lifang Zhu Nianlong Yan |
author_sort |
Yiyang Zhao |
title |
2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress |
title_short |
2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress |
title_full |
2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress |
title_fullStr |
2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress |
title_full_unstemmed |
2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress |
title_sort |
2-hydroxypropyl-β-cyclodextrin regulates the epithelial to mesenchymal transition in breast cancer cells by modulating cholesterol homeostasis and endoplasmic reticulum stress |
publisher |
MDPI AG |
series |
Metabolites |
issn |
2218-1989 |
publishDate |
2021-08-01 |
description |
Cholesterol metabolism affects endoplasmic reticulum (ER) stress and modulates epithelial-mesenchymal transition (EMT). Our previous study demonstrated that 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) attenuated EMT by blocking the transforming growth factor (TGF)-β/Smad signaling pathway and activating ER stress in MDA-MB-231 cells. To further assess the detailed mechanisms between cholesterol metabolism, ER stress, and EMT, LXR-623 (an agonist of LXRα) and simvastatin were used to increase and decrease cholesterol efflux and synthesis, respectively. Here, we found that high HP-β-CD concentrations could locally increase cholesterol levels in the ER by decreasing LXRα expression and increasing Hydroxymethylglutaryl-Coenzyme A reductase (HMGCR) expression in MDA-MB-231 and BT-549 cells, which triggered ER stress and inhibited EMT. Meanwhile, tunicamycin-induced ER stress blocked the TGF-β/Smad signaling pathway. However, low HP-β-CD concentrations can decrease the level of membrane cholesterol, enhance the TGF-β receptor I levels in lipid rafts, which helped to activate TGF-β/Smad signaling pathway, inhibit ER stress and elevate EMT. Based on our findings, the use of high HP-β-CD concentration can lead to cholesterol accumulation in the ER, thereby inducing ER stress, which directly suppresses TGF-β pathway-induced EMT. However, HP-β-CD is proposed to deplete membrane cholesterol at low concentrations and concurrently inhibit ER stress and induce EMT by promoting the TGF-β signaling pathways. |
topic |
2-hydroxypropyl-β-cyclodextrin cholesterol metabolism endoplasmic reticulum stress TGF-β/Smad signaling pathway epithelial-mesenchymal transition |
url |
https://www.mdpi.com/2218-1989/11/8/562 |
work_keys_str_mv |
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1721191583578062848 |