Down-regulation of Androgen Receptor by 3,3′-Diindolylmethane Contributes to Inhibition of Cell Proliferation and Induction of Apoptosis in Both Hormone-Sensitive LNCaP and Insensitive C4-2B Prostate Cancer Cells

Abstract

Despite the initial efficacy of androgen deprivation therapy, most patients with advanced prostate cancer eventually progress to hormone-refractory prostate cancer, for which there is no curative therapy. Previous studies from our laboratory and others have shown the antiproliferative and proapoptotic effects of 3,3 ¶-diindolylmethane (DIM) in prostate cancer cells. However, the molecular mechanism of action of DIM has not been investigated in androgen receptor (AR)-positive hormoneresponsive and -nonresponsive prostate cancer cells. Therefore, we investigated the effects of B-DIM, a formulated DIM with greater bioavailability, on AR, Akt, and nuclear factor KB (NF-KB) signaling in hormone-sensitive LNCaP (AR+) and hormone-insensitive C4-2B (AR+) prostate cancer cells. We found that B-DIM significantly inhibited cell proliferation and induced apoptosis in both cell lines. By Akt gene transfection, reverse transcription-PCR, Western blot analysis, and electrophoretic mobility shift assay, we found a potential crosstalk between Akt, NF-KB, and AR. Importantly, B-DIM significantly inhibited Akt activation, NF-KB DNA binding activity, AR phosphorylation, and the expressions of AR and prostate-specific antigen, suggesting that B-DIM could interrupt the crosstalk. Confocal studies revealed that B-DIM inhibited AR nuclear translocation, leading to the down-regulation of AR target genes. Moreover, B-DIM significantly inhibited C4-2B cell growth in a severe combined immunodeficiency-human model of experimental prostate cancer bone metastasis. These results suggest that B-DIM-induced cell proliferation inhibition and apoptosis induction are partly mediated through the downregulation of AR, Akt, and NF-KB signaling. These observations provide a rationale for devising novel therapeutic approaches for the treatment of hormone-sensitive, but more importantly, hormone-refractory prostate cancer by using B-DIM alone or in combination with other therapeutics.

3,3′-Diindolylmethane suppresses the growth of gastric cancer cells via activation of the Hippo signaling pathway

“…Despite the fact that many studies have revealed that DIM has antitumor effects in a variety of cancer cells including prostate, breast, pancreas, and esophageal cancer cells through the NF-κB, Akt, MAPK, p53, AR, and ER pathways (5,11,28,31,34,42), no information is available regarding the functional role of the Hippo signal transduction pathway in mediating DIM-induced lethality in gastric cancer cells. We found that DIM was effective in sensitizing gastric cancer cells through activation of the Hippo signaling pathway.…”

“…I3C is chemically unstable in aqueous environments and is rapidly converted to DIM, which is a major condensation product in the stomach (25)(26)(27). DIM is the predominant bioactive compound in plasma (27), and recent studies have shown that DIM has anticancer effects in both in vivo and in vitro models of various types of cancers (28)(29)(30)(31)(32)(33)(34)(35)(36)(37). However, the biological function of 3,3'-Diindolylmethane suppresses the growth of gastric cancer cells via activation of the Hippo signaling pathway DIM, and its possible use as an antitumor agent for human gastric cancer, is unknown.…”

3,3′-Diindolylmethane Induction of p75NTR-Dependent Cell Death via the p38 Mitogen-Activated Protein Kinase Pathway in Prostate Cancer Cells

“…Both I3C and DIM have been widely shown to exert anticancer effects in vivo (4) and in vitro (5,6). Use of an absorption enhanced formulation of DIM (27) in mice has shown a significant inhibition of C4-2B prostate tumors thereby validating efficacy in a tumor model of prostate cancer growth (28).…”

Ring-substituted analogs of 3,3′-diindolylmethane (DIM) induce apoptosis and necrosis in androgen-dependent and –independent prostate cancer cells

“…DIM is thought to inhibit cancer cell proliferation through several distinct yet overlapping mechanisms. By selectively binding and down-regulating AR activity, reducing AR-specific genes expression [11][12][13] and by inhibiting signaling through pro-survival regulators such as PI3K, Akt, mTOR and GSK3β, DIM inhibits cancer cell proliferation [14][15][16][17][18]. DIM also induces cancer cell death by increasing the intracellular flux of calcium ions, resulting in the induction of endoplasmic reticulum (ER) stress genes [19][20][21], and induces apoptosis through up-regulation of Fas and FasL or activation of death receptor 5 (DR5), leading to activation of caspase-dependent extrinsic apoptosis pathways [22][23][24].…”