The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic

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Blanca Herrera1, Arkaitz Carracedo, María Diez-Zaera

  • 1Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, c/José Antonio Novais s/n, 28040 Madrid, Spain.

Experimental Cell Research
|April 21, 2006
PubMed

Insights

Delta9-tetrahydrocannabinol (THC) induces cancer cell death through the CB2 receptor. This study reveals THC triggers apoptosis via ceramide production, activating the intrinsic mitochondrial pathway.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Pharmacology

Background:

  • Cannabinoids, including Delta9-tetrahydrocannabinol (THC), exhibit anti-cancer properties by inducing apoptosis in tumor cells.
  • The precise molecular mechanisms underlying cannabinoid-induced apoptosis, particularly via the CB2 receptor, remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular pathway through which Delta9-tetrahydrocannabinol (THC) induces apoptosis in leukemia cells expressing the CB2 receptor.

Main Methods:

  • Utilized the human leukemia cell line Jurkat, which uniquely expresses the CB2 receptor.
  • Investigated the role of ceramide biosynthesis and mitochondrial pathways in THC-induced apoptosis.
  • Employed CB2 antagonist SR144528, ceramide synthesis inhibitors, and caspase inhibitors to dissect the apoptotic signaling cascade.

Main Results:

  • Delta9-tetrahydrocannabinol (THC) treatment stimulated ceramide biosynthesis in a CB2 receptor-dependent manner.
  • Inhibition of ceramide synthesis blocked THC-induced mitochondrial dysfunction (hypopolarization, cytochrome c release) and caspase activation.
  • While caspase 8 was activated, its activation was post-mitochondrial, indicating the primary apoptotic signaling occurs through the intrinsic pathway.

Conclusions:

  • CB2 receptor activation by cannabinoids initiates apoptosis through a mechanism involving ceramide-dependent activation of the mitochondrial intrinsic pathway.
  • Ceramide acts upstream of mitochondrial events, preceding cytochrome c release and caspase activation in THC-induced apoptosis.

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