Targeting cannabinoid receptors to treat leukemia: role of cross-talk between extrinsic and intrinsic pathways in Delta9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells.
Targeting cannabinoid receptors has recently been shown to trigger apoptosis and offers a novel treatment modality against malignancies of the immune system. However, the precise mechanism of apoptosis in such cancers has not been previously addressed. In this study, we used human Jurkat leukemia cell lines with defects in intrinsic and extrinsic signaling pathways to elucidate the mechanism of apoptosis induced by Delta9-tetrahydrocannabinol (THC). We observed that Jurkat cells deficient in FADD or caspase-8 were partially resistant to apoptosis, while dominant-negative caspase-9 mutant cells were completely resistant to apoptosis. Use of caspase inhibitors confirmed these results. Furthermore, overexpression of Bcl-2 rendered the cells resistant to THC at early time points but not upon prolonged exposure. THC treatment led to loss of Deltapsi(m), in both wild-type and FADD-deficient Jurkat cells thereby suggesting that THC-induced intrinsic pathway was independent of FADD. THC treatment of wild-type Jurkat cells caused cytochrome c release, and cleavage of caspase-8, -9, -2, -10, and Bid. Caspase-2 inhibitor blocked THC-induced caspase-3 in wild-type Jurkat cells but not loss of Deltapsi(m). Together, these data suggest that the intrinsic pathway plays a more critical role in THC-induced apoptosis while the extrinsic pathway may facilitate apoptosis via cross-talk with the intrinsic pathway.
Lombard
Catherine
C
Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
Nagarkatti
Mitzi
M
Nagarkatti
Prakash S
PS
D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053143:Caspase 2; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D013759:Dronabinol / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000188:drug therapy*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000187:drug effects; D043882:Receptors, Cannabinoid / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D043882:Receptors, Cannabinoid; D013759:Dronabinol; D045304:Cytochromes c; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053143:Caspase 2; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases