3,3'-Diindolylmethane inhibits migration and invasion of human cancer cells through combined suppression of ERK and AKT pathways

Abstract

Metastasis of cancer is a multifactorial disease and is the main cause of death in patients with malignancy. This disease demands treatments which may target multiple dysregulated cellular pathways in cancer cells. The anti-tumor and anti-metastatic properties of natural products in cancer prevention have been confirmed by several epidemiological studies, with cruciferous vegetables being especially protective against many cancers. In this study, we evaluated the anti-carcinogenic effects of 3,3'-diindolylmethane (DIM), which is a bioactive compound present in cruciferous vegetables and a widely used dietary supplement, on events commonly observed during metastasis using in vitro adhesion, migration and invasion assays. Our results indicate that DIM inhibits human cancer cell in vitro proliferation, adhesion, migration and invasion. Western blot analyses show that this inhibition of cell proliferation by DIM is exerted by combined suppression of AKT and ERK pathways. Furthermore, DIM also leads to down-regulation of G1-S cell cycle markers: cyclin D1, cdk6 and cdk4. These findings may lead to development of a novel preventive and/or therapeutic dietary supplement for patients diagnosed with cancer or predisposed to developing certain cancers.

mTOR inhibitors sensitize thyroid cancer cells to cytotoxic effect of vemurafenib

“…Lysates were centrifuged at 14,000 rpm for 30 minutes at 4°C and each supernatant was collected. Volumes containing 10 μg protein per sample were subjected to 12% SDS-polyacrylamide gel electrophoresis as in our prior studies [ 50 , 51 ]. Proteins on gels were transferred to Immobilon-P membranes for 2 hours at 220 mA in a transfer chamber.…”

Targeted Regulation of PI3K/Akt/mTOR/NF-κB Signaling by Indole Compounds and their Derivatives: Mechanistic Details and Biological Implications for Cancer Therapy

“…Inhibition of Akt by DIM has been shown to inhibit migration and invasion of multiple cancer cells [76,77]. Such activity has also been reported in cholangiocarcinoma [78], leukemia [79] and cervical cancer [80] cells.…”

Attenuation of multi-targeted proliferation-linked signaling by 3,3′-diindolylmethane (DIM): From bench to clinic

“…The molecular link between other key G1 acting cell cycle components being inhibited by DIM have been reported in human cancer cell lines from prostate and thyroid by Garipatty et.al. [30] and Rajoria S et.al [31]. Included among these components are CDK4, CDK6 and cyclin D. Data from other investigators surmised the effect of DIM in regulation of cell cycle in other cell lines such as colon, thyroid, breast and ovarian cancer cells.…”

“…In addition, Wang et al from our laboratory reported that DIM inhibit the growth of breast cancer cell lines over-expressing Her-2 and activated Akt via the modulation of the PI3K/Akt pathway and p27 Kip1 independent of estrogen receptor status [74], suggesting that DIM is a front runner pleiotropic agent, and thus could be useful for the prevention of tumor progression and/or treatment of cancers that have defects in multiple genes. In spot of clinical drug development Rajoria et al recently pointed to the inhibition of cell proliferation by DIM is exerted by the combined suppression of Akt and ERK pathways [31]. …”