Pegylated Phospholipid Micelles Induce Endoplasmic Reticulum-Dependent Apoptosis of Cancer Cells but not Normal Cells

The rapid developments in nanotechnology have brought with them a deep concern over the safety of nanomaterials. Investigating the molecular mechanisms underlying their toxicity in different cell lines will help us better understand and apply nanomaterials appropriately. Poly(ethylene glycol)-phosphoethanolamine (PEG-PE) is an FDA-approved nonionic diblock copolymer and is widely used in drug delivery systems. Here, we find that PEG-PE accumulates in the endoplasmic reticulum (ER) and induces ER stress and that cancer cells and normal cells have different cell fates as a result of this stress. In A549 cancer cells, PEG-PE damages ER functions and triggers apoptosis by activating proapoptotic UPR signaling and high expression of cell death effector CHOP and proapoptotic Bax/Bak. In addition, PEG-PE-induced ER stress also up-regulates lipid synthesis and triggers lipid droplet formation in cancer cells. By contrast, in MRC-5 and 293T cells, high expression of the UPR feedback protein GADD34 which inhibits proapoptotic UPR signaling, and antiapoptotic Bcl-2 and Bcl-xl which down-regulate Bax/Bak, protect these normal cells from PEG-PE-induced apoptosis. When gadd34, bcl-2, or bcl-xl is knocked down, apoptosis occurs in PEG-PE-treated normal cells. In summary, we demonstrate the safety of PEG-PE in normal cells and elaborate the molecular mechanism underlying its nanotoxicity in cancer cells. This study implies PEG-PE-based drug delivery system has the potential to alter the sensitivity of cancer cells to some chemotherapeutic agents by selectively activating unfolded protein response (UPR) in cancer cells, and it also provides a useful foundation for research on ER stress-induced nanotoxicity and other lipid-based nanomaterials.