Pathways to Paraptosis After ER Photodamage in OVCAR‐5 Cells

A death mode termed paraptosis is initiated by photodamage to the endoplasmic reticulum (ER). This is characterized by an extensive pattern of cytoplasmic vacuole formation and leads to a gradual loss of cytoplasm and of viability. Many photosensitizers in clinical use target sub‐cellular organelles that include the ER and can, therefore, invoke paraptosis as well as apoptosis. In this study, we explore pathways to paraptosis in OVCAR‐5, an ovarian cancer cell line of human origin. At low PDT doses, the route to paraptosis follows the pattern that occurs after chemotherapy, that is, a pattern of vacuole formation that can be suppressed by MAPK antagonists or inhibition of new protein synthesis. At PDT doses clinically pertinent for tumor eradication, the pathway to paraptosis appears to be independent of these factors. In addition to morphologic changes, translocation of the nuclear protein HMGB1(high mobility group protein B1) to the cell periphery has been described as a potential marker for drug‐induced paraptosis. This occurs to only a very minor extent after a lethal PDT dose that targets the ER. It appears that a lethal level of ER photodamage can initiate a different pathway to paraptosis, perhaps associated with ER protein cross‐linking.