title: Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by translocation of Bad to mitochondria.
abstract: Plant-derived cannabinoids, including Delta9-tetrahydrocannabinol (THC), induce apoptosis in leukemic cells, although the precise mechanism remains unclear. In the current study, we investigated the effect of THC on the upstream and downstream events that modulate the extracellular signal-regulated kinase (ERK) module of mitogen-activated protein kinase pathways primarily in human Jurkat leukemia T cells. The data showed that THC down-regulated Raf-1/mitogen-activated protein kinase/ERK kinase (MEK)/ERK/RSK pathway leading to translocation of Bad to mitochondria. THC also decreased the phosphorylation of Akt. However, no significant association of Bad translocation with phosphatidylinositol 3-kinase/Akt and protein kinase A signaling pathways was noted when treated cells were examined in relation to phosphorylation status of Bad by Western blot and localization of Bad to mitochondria by confocal analysis. Furthermore, THC treatment decreased the Bad phosphorylation at Ser(112) but failed to alter the level of phospho-Bad on site Ser(136) that has been reported to be associated with phosphatidylinositol 3-kinase/Akt signal pathway. Jurkat cells expressing a constitutively active MEK construct were found to be resistant to THC-mediated apoptosis and failed to exhibit decreased phospho-Bad on Ser(112) as well as Bad translocation to mitochondria. Finally, use of Bad small interfering RNA reduced the expression of Bad in Jurkat cells leading to increased resistance to THC-mediated apoptosis. Together, these data suggested that Raf-1/MEK/ERK/RSK-mediated Bad translocation played a critical role in THC-induced apoptosis in Jurkat cells.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, USA.
authors.forename: Wentao
authors.initials: W
authors.lastname: Jia
authors.forename: Venkatesh L
authors.initials: VL
authors.lastname: Hegde
authors.forename: Narendra P
authors.initials: NP
authors.lastname: Singh
authors.forename: Daniel
authors.initials: D
authors.lastname: Sisco
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Nagarkatti
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation; D013759:Dronabinol / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000378:metabolism / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D051025:bcl-Associated Death Protein / Q000378:metabolism* / Q000502:physiology
chemical_list: C494819:BAD protein, human; D043882:Receptors, Cannabinoid; D051025:bcl-Associated Death Protein; D013759:Dronabinol; D037342:Pertussis Toxin; D011494:Protein Kinases; D019908:Proto-Oncogene Proteins c-raf; D019893:Ribosomal Protein S6 Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate