Δ9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by translocation of bad to mitochondria

Wentao Jia, Venkatesh L. Hegde, Narendra P. Singh, Daniel Sisco, Steven Grant, Mitzi Nagarkatti, Prakash S. Nagarkatti

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Plant-derived cannabinoids, including Δ9-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 Ser112 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 Ser112 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.

Original languageEnglish (US)
Pages (from-to)549-562
Number of pages14
JournalMolecular Cancer Research
Volume4
Issue number8
DOIs
StatePublished - Aug 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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