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-beta-cyclodextrin (HP-beta-CD) attenuated EMT by blocking the transforming growth factor (TGF)-beta/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 LXR alpha) and simvastatin were used to increase and decrease cholesterol efflux and synthesis, respectively. Here, we found that high HP-beta-CD concentrations could locally increase cholesterol levels in the ER by decreasing LXR alpha 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-beta/Smad signaling pathway. However, low HP-beta-CD concentrations can decrease the level of membrane cholesterol, enhance the TGF-beta receptor I levels in lipid rafts, which helped to activate TGF-beta/Smad signaling pathway, inhibit ER stress and elevate EMT. Based on our findings, the use of high HP-beta-CD concentration can lead to cholesterol accumulation in the ER, thereby inducing ER stress, which directly suppresses TGF-beta pathway-induced EMT. However, HP-beta-CD is proposed to deplete membrane cholesterol at low concentrations and concurrently inhibit ER stress and induce EMT by promoting the TGF-beta signaling pathways.

Automated summary

High concentrations of HP-β-CD can increase cholesterol levels in the ER, trigger ER stress, and inhibit EMT by decreasing LXR alpha expression. On the other hand, low concentrations of HP-β-CD can reduce membrane cholesterol levels, activate the TGF-beta/Smad signaling pathway, inhibit ER stress, and promote EMT by enhancing TGF-beta receptor I levels in lipid rafts.