3,3'-diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress-dependent upregulation of DR5.
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.
Abdelrahim
Maen
M
Institute of Biosciences and Technology, The Texas A&M University System Health Science Center, 2121 W. Holcombe Boulevard, Houston, TX 77030, USA.
Newman
Kristen
K
Vanderlaag
Kathy
K
Samudio
Ismael
I
Safe
Stephen
S
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis; D004721:Endoplasmic Reticulum / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000502:physiology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D016588:Anticarcinogenic Agents; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007211:Indoles; D018832:Molecular Chaperones; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C505639:TNFRSF10B protein, human; D051742:Transcription Factor CHOP; C016392:3,3'-diindolylmethane