3,3'-diindolylmethane induction of p75NTR-dependent cell death via the p38 mitogen-activated protein kinase pathway in prostate cancer cells.
The p75(NTR) functions as a tumor suppressor in prostate epithelial cells, where its expression declines with progression to malignant cancer. Previously, we showed that treatment with the nonsteroidal anti-inflammatory drug, indomethacin, induced p75(NTR) expression in the T24 cancer cell line leading to p75(NTR)-mediated decreased survival. Utilizing the indole moiety of indomethacin as a pharmacophore, we identified in rank-order with least efficacy, ketorolac, etodolac, indomethacin, 5-methylindole-3-acetic acid, indole-3-carbinol, and 3,3'-diindolylmethane (DIM) exhibiting greatest activity for induction of p75(NTR) levels and inhibition of cell survival. Prostate (PC-3, DU-145) and bladder (T24) cancer cells were more sensitive to DIM induction of p75(NTR)-associated loss of survival than breast (MCF7) and fibroblast (3T3) cells. Transfection of the PC-3 prostate cell line with a dominant-negative form of p75(NTR) before DIM treatment significantly rescued cell survival demonstrating a cause and effect relationship between DIM induction of p75(NTR) levels and inhibition of survival. Furthermore, siRNA knockdown of the p38 mitogen-activated protein kinase (MAPK) protein prevented induction of p75(NTR) by DIM in the PC-3 prostate cell line. DIM treatment induced phosphorylation of p38 MAPK as early as within 1 minute. Collectively, we identify DIM as an indole capable of inducing p75(NTR)-dependent apoptosis via the p38 MAPK pathway in prostate cancer cells.
Khwaja
Fatima S
FS
Department of Biochemistry, the Vincent T Lombardi Comprehensive Cancer Center, Georgetown University Medical, University of the District of Columbia, Washington, DC 20057-1436, USA.
Wynne
Shehla
S
Posey
Isadora
I
Djakiew
Daniel
D
D016475:3T3 Cells / Q000187:drug effects; D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019607:Brassicaceae; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D004441:Ecdysterone / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D007211:Indoles; C484065:NGFR protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D004441:Ecdysterone; C008999:ponasterone A; D048051:p38 Mitogen-Activated Protein Kinases; C016392:3,3'-diindolylmethane