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Cancer Res. 2006 Jul 1;66(13):6748-55.
Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stressrelated genes.
Carracedo A1, Gironella M, Lorente M, Garcia S, Guzmán M, Velasco G, Iovanna JL.
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Abstract
Pancreatic adenocarcinomas are among the most malignant forms of cancer and, therefore, it is of especial interest to set
new strategies aimed at improving the prognostic of this deadly disease. The present study was undertaken to investigate
the action of cannabinoids, a new family of potential antitumoral agents, in pancreatic cancer. We show that cannabinoid
receptors are expressed in human pancreatic tumor cell lines and tumor biopsies at much higher levels than in normal
pancreatic tissue. Studies conducted with MiaPaCa2 and Panc1 cell lines showed that cannabinoid administration (a)
induced apoptosis, (b) increased ceramide levels, and (c) up-regulated mRNA levels of the stress protein p8. These effects
were prevented by blockade of the CB(2) cannabinoid receptor or by pharmacologic inhibition of ceramide synthesis de
novo. Knockdown experiments using selective small interfering RNAs showed the involvement of p8 via its downstream
endoplasmic reticulum stress-related targets activating transcription factor 4 (ATF-4) and TRB3 in Delta(9)tetrahydrocannabinol-induced apoptosis. Cannabinoids also reduced the growth of tumor cells in two animal models of
pancreatic cancer. In addition, cannabinoid treatment inhibited the spreading of pancreatic tumor cells. Moreover,
cannabinoid administration selectively increased apoptosis and TRB3 expression in pancreatic tumor cells but not in
normal tissue. In conclusion, results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via
a CB(2) receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stressrelated genes ATF-4 and TRB3. These findings may contribute to set the basis for a new therapeutic approach for the
treatment of pancreatic cancer.
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PMID: 16818650 [PubMed - indexed for MEDLINE]
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