Hydroxypropyl-β-cyclodextrin attenuates the epithelial-to-mesenchymal transition via endoplasmic reticulum stress in MDA-MB-231 breast cancer cells

The epithelial-to-mesenchymal transition (EMT) has been reported to serve vital roles in regulating the progress of cancer metastasis. In addition, lipid rafts enriched in sphingolipids and cholesterol serve important roles in physiological and biochemical processes as a signaling platform. The present study explored the effects of hydroxypropyl-β-cyclodextrin (HP-β-CD), a cholesterol-depleting agent of lipid rafts, on the transforming growth factor (TGF)-β/Smad signaling pathway and endoplasmic reticulum (ER) stress in mediating EMT in MDA-MB-231 breast cancer cells. HP-β-CD treatment inhibited TGF-β1-induced EMT, based on increased expression of E-cadherin and decreased expression of vimentin. HP-β-CD reduced the expression of the TGF receptor TβRI and blocked the phosphorylation of Smad2. In addition, HP-β-CD increased the expression of ER stress-related proteins (binding immunoglobulin protein and activating transcription factor 6), but TGF-β1 could reverse these changes. Sodium 4-phenylbutyrate, an inhibitor of ER stress, suppressed these effects of HP-β-CD on EMT and TGF-β/Smad signaling pathway inhibition in breast cancer cells. Thus, HP-β-CD can block the TGF-β/Smad signaling pathway via diminishing the expression of TβRI which helps to activate ER stress and attenuate EMT in MDA-MB-231 cells, highlighting a potential target of lipid rafts for breast cancer treatment.