title: Identification of the couple GSK3α/c-Myc as a new regulator of hexokinase II in benzo[a]pyrene-induced apoptosis.
abstract: The early apoptotic events induced by environmental pollutants with carcinogenic properties are poorly understood. Here, we focus on the early cytotoxic effects of benzo[a]pyrene (B[a]P). In F258 rat hepatic epithelial cells, B[a]P induces intrinsic apoptosis via a mitochondrial dysfunction characterized by the release of hexokinase II (HKII) from the mitochondria. Cancer cells often have an anomalous cell energy metabolism; since HKII dysfunction regulates B[a]P-induced apoptosis in F258 cells, but may also alter cell energy metabolism, HKII release from the mitochondria may represent an important B[a]P-related carcinogenic issue. Thus in the present study, we aimed at deciphering the mechanisms underlying HKII dysfunction upon B[a]P exposure. We show that while glycogen synthase kinase 3 beta (GSK3β) regulated the expression of HKII at the transcriptional level, glycogen synthase kinase 3 alpha (GSK3α) was involved in B[a]P-induced apoptosis via a decrease in c-Myc expression. The reduced level of c-Myc caused the relocation of HKII from the mitochondria to the cytosol, thereby being involved in the formation of reactive oxygen species and apoptosis. In conclusion, we show that the couple GSK3α/c-Myc plays a key role in B[a]P-induced early apoptotic cell signaling via HKII dysfunction.
authors.affiliation: EA SeRAIC, Equipe labellisée Ligue contre le Cancer, IRSET, Université de Rennes 1, IFR 140, Rennes, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Dendelé
authors.forename: Xavier
authors.initials: X
authors.lastname: Tekpli
authors.forename: Odile
authors.initials: O
authors.lastname: Sergent
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Dimanche-Boitrel
authors.forename: Jørn A
authors.initials: JA
authors.lastname: Holme
authors.forename: Laurence
authors.initials: L
authors.lastname: Huc
authors.forename: Dominique
authors.initials: D
authors.lastname: Lagadic-Gossmann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D004785:Environmental Pollutants / Q000633:toxicity*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006593:Hexokinase / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats
chemical_list: D002273:Carcinogens; D004785:Environmental Pollutants; D016271:Proto-Oncogene Proteins c-myc; D001564:Benzo(a)pyrene; D006593:Hexokinase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha