3,3'-diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress-dependent upregulation of DR5.

Abstract

3,3'-Diindolylmethane (DIM), ring-substituted DIMs and 1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methanes (C-DIMs) inhibit growth of Panc-1 and Panc-28 pancreatic cancer cells. Although DIMs (diarylmethanes) and selected C-DIMs (triarylmethanes), such as the p-t-butyl derivative (DIM-C-pPhtBu), activate the aryl hydrocarbon receptor and peroxisome proliferator-activated receptor gamma, respectively, this study shows that both DIM and DIM-C-pPhtBu induce common receptor-independent pathways. Both DIM and DIM-C-pPhtBu increased endoplasmic reticulum (ER) staining and ER calcium release in Panc-1 cells, and this was accompanied by increased expression of glucose related protein 78 and C/EBP homologous transcription factor (CHOP/GADD153) proteins. Similar results were observed after treatment with thapsigargin (Tg), a prototypical inducer of ER stress. The subsequent downstream effects of DIM/DIM-C-pPhtBu- and Tg-induced ER stress included CHOP-dependent induction of death receptor DR5 and subsequent cleavage of caspase 8, caspase 3, Bid and PARP. Activation of both receptor-dependent and receptor-independent (ER stress) pathways by DIM and DIM-C-pPhtBu in pancreatic cancer cells enhances the efficacy and potential clinical importance of these compounds for cancer chemotherapeutic applications.

• Authors: Maen Abdelrahim, Kristen Newman, Kathy Vanderlaag, Ismael Samudio, Stephen Safe
• Journal: Carcinogenesis (Carcinogenesis) Vol. 27 Issue 4 Pg. 717-28 (Apr 2006) ISSN: 0143-3334 [Print] England
• PMID: 16332727 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anticarcinogenic Agents
• DDIT3 protein, human
• Endoplasmic Reticulum Chaperone BiP
• Heat-Shock Proteins
• Indoles
• Molecular Chaperones
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor
• TNFRSF10B protein, human
• Transcription Factor CHOP
• 3,3'-diindolylmethane

Topics

• Anticarcinogenic Agents (pharmacology)
• Apoptosis
• Endoplasmic Reticulum (physiology)
• Endoplasmic Reticulum Chaperone BiP
• Heat-Shock Proteins (biosynthesis, physiology)
• Humans
• Indoles (pharmacology)
• Molecular Chaperones (biosynthesis, physiology)
• Pancreatic Neoplasms (genetics, pathology)
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor (biosynthesis)
• Transcription Factor CHOP (biosynthesis, physiology)
• Tumor Cells, Cultured
• Up-Regulation