title: Alpha-tocopheryl succinate induces rapid and reversible phosphatidylserine externalization in histiocytic lymphoma through the caspase-independent pathway.
abstract: Phosphatidylserine (PS) externalization is a key feature of apoptotic cell death and plays an important role in clearance of apoptotic cells by phagocytes. PS externalization during apoptosis is generally an irreversible event mediated by caspase activation and is accompanied by other apoptotic events. We report here that an apoptosis inducer alpha-tocopheryl succinate (TOS) can induce PS externalization that is independent of apoptosis and reversible in the absence of fetal bovine serum (FBS) in histiocytic lymphoma U937 cells. In the presence of FBS, TOS induced PS externalization via a caspase-dependent mechanism accompanied by mitochondrial depolarization, cell shrinkage, increase of caspase-3 activity, and chromatin condensation. In contrast, in the absence of FBS, TOS induced the rapid PS externalization which was not accompanied by other apoptotic events. The PS externalization was reversible by removing TOS and was not involved in Ca(2+)-dependent scramblase activation and thiol oxidation of aminophospholipid translocase. A similar PS externalization was also induced by cholesteryl hemisuccinate (CS), the other succinate ester. These results suggested that the mechanism of TOS- and CS-induced PS externalization in the absence of FBS was different from it occurring during typical apoptosis.
authors.affiliation: Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Okayama, 700-8558, Japan. fujita00@md.okayama-u.ac.jp
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fujita
authors.forename: Daisuke
authors.initials: D
authors.lastname: Shiva
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Utsumi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ogino
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ogawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Abe
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Yasuda
authors.forename: Kozo
authors.initials: K
authors.lastname: Utsumi
authors.forename: Junzo
authors.initials: J
authors.lastname: Sasaki
mesh_terms: D017209:Apoptosis; D001692:Biological Transport / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002788:Cholesterol Esters / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D006801:Humans; D010718:Phosphatidylserines / Q000378:metabolism*; D024502:alpha-Tocopherol / Q000494:pharmacology*
chemical_list: D002788:Cholesterol Esters; D016895:Culture Media, Serum-Free; D010718:Phosphatidylserines; D020169:Caspases; D024502:alpha-Tocopherol; C013440:cholesteryl succinate