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Carcinogenesis Advance Access published online on December 6, 2005
Carcinogenesis, doi:10.1093/carcin/bgi270
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received July 18, 2005
Revised October 6, 2005
Accepted November 9, 2005

CANCER BIOLOGY

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

Maen Abdelrahim 1, Kristen Newman 1, Kathy Vanderlaag 2, Ismael Samudio 3, and Stephen Safe 4 *

1 Institute of Biosciences and Technology, The Texas A&M University System Health Science Center, 2121 W. Holcombe Blvd., Houston, TX 77030
2 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843
3 Department of Blood and Marrow Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
4 Institute of Biosciences and Technology, The Texas A&M University System Health Science Center, 2121 W. Holcombe Blvd., Houston, TX 77030; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843

* To whom correspondence should be addressed.
Stephen Safe, E-mail: ssafe{at}cvm.tamu.edu


  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} (PPAR{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 (GRP78) 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 -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.

Keywords: 3,3'-diindolylmethane; cancer; ER stress; apoptosis; DIM.
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