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1,1‐bis(3′‐indolyl)‐1‐( p ‐methoxyphenyl)methane activates Nur77‐independent proapoptotic responses in colon cancer cells
Author(s) -
Cho Sung Dae,
Lei Ping,
Abdelrahim Maen,
Yoon Kyungsil,
Liu Shengxi,
Guo Jingjing,
Papineni Sabitha,
Chintharlapalli Sudhakar,
Safe Stephen
Publication year - 2008
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20378
Subject(s) - nerve growth factor ib , biology , apoptosis , cancer research , microbiology and biotechnology , kinase , signal transduction , small interfering rna , nuclear receptor , transcription factor , transfection , biochemistry , gene
1,1‐Bis(3′‐indolyl)‐1‐( p ‐methoxyphenyl)methane (DIM‐C‐pPhOCH 3 ) is a methylene‐substituted diindolylmethane (C‐DIM) analog that activates the orphan receptor nerve growth factor‐induced‐Bα (NGFI‐Bα, Nur77). RNA interference studies with small inhibitory RNA for Nur77 demonstrate that DIM‐C‐pPhOCH 3 induces Nur77‐dependent and ‐independent apoptosis, and this study has focused on delineating the Nur77‐independent proapoptotic pathways induced by the C‐DIM analog. DIM‐C‐pPhOCH 3 induced caspase‐dependent apoptosis in RKO colon cancer cells through decreased mitochondrial membrane potential which is accompanied by increased mitochondrial bax/bcl‐2 ratios and release of cytochrome c into the cytosol. DIM‐C‐pPhOCH 3 also induced phosphatidylinositol‐3‐kinase‐dependent activation of early growth response gene‐1 which, in turn, induced expression of the proapoptotic nonsteroidal anti‐inflammatory drug‐activated gene‐1 (NAG1) in RKO and SW480 colon cancer cells. Moreover, DIM‐C‐pPhOCH 3 also induced NAG‐1 expression in colon tumors in athymic nude mice bearing RKO cells as xenografts. DIM‐C‐pPhOCH 3 also activated the extrinsic apoptosis pathway through increased phosphorylation of c‐ jun N‐terminal kinase which, in turn, activated C/EBP homologous transcription factor (CHOP) and death receptor 5 (DR5). Thus, the effectiveness of DIM‐C‐pPhOCH 3 as a tumor growth inhibitor is through activation of Nur77‐dependent and ‐independent pathways. © 2007 Wiley‐Liss, Inc.