Regulation of YAP through an Akt-dependent process by 3, 3′-diindolylmethane in human colon cancer cells

Abstract

Cancer development is a complex process governed by the interaction of several signaling pathways. The Hippo and PI3K/Akt pathways have been shown to play a critical role in controlling tissue growth involved in the regulation of cell proliferation. 3, 3'-diindolylmethane (DIM) is a natural compound that selectively kills cancer cells without causing toxicity to normal cells. This study aims to investigate whether DIM has an effect on the Hippo signaling pathway mediated via the PI3K/Akt signaling pathway in colon cancer cells. Our study provides new insights into the mechanisms of crosstalk between Hippo signaling and the Akt pathway controlling cell proliferation by PI3K inhibitor and DIM treatment in colon cancer cells. DIM strongly potentiates the lethality of LY294002 in HCT116 cells and inhibits proliferation of colon cancer cells via inactivation of Akt and YAP. Thus, DIM has dramatic therapeutic effects when it is combined with the PI3K inhibitor in the treatment of colon cancer cells. These findings highlight the potential usefulness of DIM and can help develop therapeutic strategies for the prevention and treatment of colon cancer.

3,3′-Diindolylmethane potentiates paclitaxel-induced antitumor effects on gastric cancer cells through the Akt/FOXM1 signaling cascade

“…DIM, a non-toxic dietary chemopreventive agent, has been investigated for preventing, inhibiting and reversing the progression of various types of cancer (32). Many studies have suggested that DIM is strongly associated with tumor growth suppression mediated by several signaling pathways in human carcinomas (9,(17)(18)(19)(20)24,32). We found that DIM significantly inhibited gastric cancer cell growth in a dose-dependent manner and potentiated the antitumor effects of paclitaxel in gastric cancer cells.…”

“…Turati et al (12) and Guercio et al (16) reported that high allium vegetable consumption reduces gastric cancer risk, and a high intake of cruciferous vegetables was found to be inversely associated with the risk of gastric cancer in humans in a study by Wu et al (15). The compound 3,3'-diindolylmethane (DIM) is a component of cruciferous vegetables that inhibits tumor growth through induction of apoptosis in various types of cancer cells (17)(18)(19)(20). Our previous study demonstrated that DIM suppressed gastric cancer cell growth via activation of the Hippo signaling pathway (17).…”

“…Colony formation assays were performed as previously described (17,19). Cells were seeded at 5x10 4 cells/plate with or without DIM and paclitaxel, grown until visible colonies appeared and observed under microscopy to count colonies.…”

“…SNU638 cells were treated with DIM (0, 50, 75 or 100 µM), followed by 72 h of growth with or without paclitaxel (0, 50, 75 or 100 nM). Cells with or without DIM and paclitaxel were harvested and suspended in lysis buffer (Intron Biotechnology, Inc.) as previously described (17,19,31). The protein concentration was determined using BSA protein assay kits (Pierce, Rockford, IL, USA).…”

Protective Effect of 3, 3-Diindolylmethane on Bisphenol A Activated GPR30, RAS, PI3K/Akt Estrogenic Signaling Pathway in Female Sprague-Dawley Rats

“…The previous study reported that Hippo signaling and Akt pathway controlling cell proliferation by PI3K inhibitor and DIM treatment in colon cancer cells [15]. In addition, DIM induced G1 cell cycle arrest that coincided with a strong induction of P21 gene expression and promoter activity in both estrogen responsive and nonresponsive breast cancer cells [16].…”