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Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes.
Cancer Res. 2006 Jul 01; 66(13):6748-55.CR

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 stress-related genes ATF-4 and TRB3. These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, c/José Antonio Novais s/n, 28040 Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16818650

Citation

Carracedo, Arkaitz, et al. "Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells Via Endoplasmic Reticulum Stress-related Genes." Cancer Research, vol. 66, no. 13, 2006, pp. 6748-55.
Carracedo A, Gironella M, Lorente M, et al. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res. 2006;66(13):6748-55.
Carracedo, A., Gironella, M., Lorente, M., Garcia, S., Guzmán, M., Velasco, G., & Iovanna, J. L. (2006). Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Research, 66(13), 6748-55.
Carracedo A, et al. Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells Via Endoplasmic Reticulum Stress-related Genes. Cancer Res. 2006 Jul 1;66(13):6748-55. PubMed PMID: 16818650.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. AU - Carracedo,Arkaitz, AU - Gironella,Meritxell, AU - Lorente,Mar, AU - Garcia,Stephane, AU - Guzmán,Manuel, AU - Velasco,Guillermo, AU - Iovanna,Juan L, PY - 2006/7/5/pubmed PY - 2006/9/8/medline PY - 2006/7/5/entrez SP - 6748 EP - 55 JF - Cancer research JO - Cancer Res VL - 66 IS - 13 N2 - 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 stress-related genes ATF-4 and TRB3. These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/16818650/Cannabinoids_induce_apoptosis_of_pancreatic_tumor_cells_via_endoplasmic_reticulum_stress_related_genes_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16818650 DB - PRIME DP - Unbound Medicine ER -