Identification of the couple GSK3α/c-Myc as a new regulator of hexokinase II in benzo[a]pyrene-induced apoptosis.

Béatrice Dendelé (1) , Xavier Tekpli (1) , Odile Sergent (1) , Marie-Thérèse Dimanche-Boitrel (2) , Jørn A. Holme (3) , Laurence Huc (1) , Dominique Lagadic-Gossmann (2)

1 Irset - Institut de recherche en santé, environnement et travail
2 SMS - Stress, membrane et signalisation
3 Division of Environmental Medicine

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.

Mots clés: GSK3; Hexokinase II; c-Myc; Apoptosis; Mitochondria; Benzo[a]pyrene; NHE1

Domaines: Toxicologie

Béatrice Dendelé, Xavier Tekpli, Odile Sergent, Marie-Thérèse Dimanche-Boitrel, Jørn A. Holme, et al.. Identification of the couple GSK3α/c-Myc as a new regulator of hexokinase II in benzo[a]pyrene-induced apoptosis.. Toxicology in Vitro, 2012, 26 (1), pp.94-101. ⟨10.1016/j.tiv.2011.11.001⟩. ⟨hal-00682104⟩