TY - JOUR
T1 - 3,3′-Diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress-dependent upregulation of DR5
AU - Abdelrahim, Maen
AU - Newman, Kristen
AU - Vanderlaag, Kathy
AU - Samudio, Ismael
AU - Safe, Stephen
N1 - Funding Information:
This work was supported by the National Institutes of Health (CA108178 and ES09106), M.D. Anderson Cancer Center (P20-CA-10193) and the Texas Agricultural Experiment Station.
PY - 2006/4
Y1 - 2006/4
N2 - 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 γ, 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.
AB - 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 γ, 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.
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U2 - 10.1093/carcin/bgi270
DO - 10.1093/carcin/bgi270
M3 - Article
C2 - 16332727
AN - SCOPUS:33645294370
SN - 0143-3334
VL - 27
SP - 717
EP - 728
JO - Carcinogenesis
JF - Carcinogenesis
IS - 4
ER -