2-羟丙基-β-环糊精通过调节胆固醇稳态和内质网应激来调节乳腺癌细胞的上皮向间充质转化,Metabolites

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2-羟丙基-β-环糊精通过调节胆固醇稳态和内质网应激来调节乳腺癌细胞的上皮向间充质转化
Metabolites ( IF 3.4 ) Pub Date : 2021-08-23 , DOI: 10.3390/metabo11080562
Yiyang Zhao ₁ , Linkang He _{1,

2} , Tian Wang ₁ , Lifang Zhu ₁ , Nianlong Yan ₁

Affiliation

胆固醇代谢影响内质网 (ER) 应激并调节上皮间质转化 (EMT)。我们之前的研究表明，2-羟丙基-β-环糊精 (HP-β-CD) 通过阻断转化生长因子 (TGF)-β/Smad 信号通路和激活 MDA-MB-231 细胞中的内质网应激来减弱 EMT。为了进一步评估胆固醇代谢、ER 应激和 EMT 之间的详细机制，LXR-623（LXRα 的激动剂）和辛伐他汀分别用于增加和减少胆固醇流出和合成。在这里，我们发现高 HP-β-CD 浓度可以通过降低 LXRα 表达和增加 MDA-MB-231 和 BT-549 细胞中羟甲基戊二酰辅酶 A 还原酶 (HMGCR) 的表达来局部增加 ER 中的胆固醇水平，从而触发 ER压力和抑制 EMT。同时，衣霉素诱导的内质网应激阻断了 TGF-β/Smad 信号通路。然而，低HP-β-CD浓度可以降低膜胆固醇水平，提高脂筏中TGF-β受体I的水平，这有助于激活TGF-β/Smad信号通路，抑制内质网应激，提高EMT。根据我们的研究结果，使用高浓度 HP-β-CD 会导致内质网中胆固醇积累，从而诱导内质网应激，从而直接抑制 TGF-β 通路诱导的 EMT。然而，HP-β-CD 被提议在低浓度下消耗膜胆固醇，同时通过促进 TGF-β 信号通路抑制 ER 应激和诱导 EMT。提高脂筏中 TGF-β 受体 I 的水平，这有助于激活 TGF-β/Smad 信号通路，抑制 ER 应激并提高 EMT。根据我们的研究结果，使用高浓度 HP-β-CD 会导致内质网中胆固醇积累，从而诱导内质网应激，从而直接抑制 TGF-β 通路诱导的 EMT。然而，HP-β-CD 被提议在低浓度下消耗膜胆固醇，同时通过促进 TGF-β 信号通路抑制 ER 应激和诱导 EMT。提高脂筏中 TGF-β 受体 I 的水平，这有助于激活 TGF-β/Smad 信号通路，抑制 ER 应激并提高 EMT。根据我们的研究结果，使用高浓度 HP-β-CD 会导致内质网中胆固醇积累，从而诱导内质网应激，从而直接抑制 TGF-β 通路诱导的 EMT。然而，HP-β-CD 被提议在低浓度下消耗膜胆固醇，同时通过促进 TGF-β 信号通路抑制 ER 应激和诱导 EMT。

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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 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.

更新日期：2021-08-23

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