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3,3'-Diindolylmethane Induction of p75^NTR-Dependent Cell Death via the p38 Mitogen-Activated Protein Kinase Pathway in Prostate Cancer Cells

Authors' Affiliations: ¹ The Department of Biochemistry and Molecular and Cellular Biology and the Vincent T. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center and ² The Department of Chemistry and Physics, University of the District of Columbia, Washington, D.C.

Requests for reprints: Daniel Djakiew, Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, 3900 Reservoir Road Northwest, Washington, D.C. 20057-1436. Phone: 202-687-1203; Fax: 202-687-1823; E-mail: djakiewd{at}georgetown.edu.

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.

Key Words: DIM • p75^NTR • p38 MAPK • indoles