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

Abstract

Abstract. Recent studies have revealed that 3,3-diindolylmethane (DIM) has antitumor effects in both in vivo and in vitro tumor models. However, the biological function of DIM in human gastric cancer cells is unknown. Genetic and biological studies have confirmed the importance of the novel Hippo tumor-suppressor pathway in regulating cell proliferation, apoptosis, organ size and tumorigenesis in mammals. Thus, the purpose of this study was to investigate the cytotoxic effects of DIM in human gastric cancer cells and to elucidate whether DIM induces cell death by activating the Hippo signaling pathway. Two human gastric cancer cell lines (SNU-1 and SNU-484) were used to investigate the DIM response. DIM significantly inhibited the proliferation of human gastric cancer cells in a dose-dependent manner. The percentage of G1 phase cells increased 24 h following DIM treatment. DIM reduced CDK2, CDK4, CDK6 and cyclin D1 protein levels, while increasing p53 protein levels. DIM induced the levels of cleaved poly(ADP-ribose) polymerase, cleaved-caspase-9, and diminished pro-caspase-3 protein production. In addition, DIM increased pLATS1, Mob1, pMob1, pYAP and Ras association domain family 1 (RASSF1) protein levels and reduced Yap protein production levels. DIM stimulated the binding of RASSF1 with the Mst1/2-LATS1-Mob1 complex, promoting an active Hippo signaling pathway and favoring YAP phosphorylation (pYAP) that inactivates cell proliferation. Furthermore, DIM inhibited the growth of human gastric tumors in a xenograft mouse model. These results indicate that DIM suppresses the growth of gastric cancer cells by activating the Hippo signaling pathway.

3,3′-Diindolylmethane Ameliorates Experimental Autoimmune Encephalomyelitis by Promoting Cell Cycle Arrest and Apoptosis in Activated T Cells through MicroRNA Signaling Pathways

“…However, these studies have predominantly involved the development of cancer (Lerner et al, 2012;Li et al, 2013). Similarly, studies have shown that miR-22 can protect against cancer as illustrated by the fact that overexpression of miR-22 is associated with reduced tumor growth, volume, and decreased migration of tumor cells (Ling et al, 2012).…”

“…More recently, the use of plant-derived indoles, such as 3,39-diindolylmethane (DIM), which are found in cruciferous vegetables, and other similarly structured compounds, have been reported as a potential therapeutic modality against inflammatory disorders (Busbee et al, 2013). Data from various cancer studies, which include prostate (Nachshon-Kedmi et al, 2003), colon (Lerner et al, 2012), and gastric (Li et al, 2013) cancers, have collectively suggested that DIM also acts on a number of molecular pathways centered on cellular proliferation and survival to mediate its effects. In contrast, the immunomodulatory and antiproliferative properties of DIM have not been well studied, particularly in regards to autoimmune diseases.…”

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

“…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).…”

“…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). DIM was found to inhibit gastric cancer cell growth by modulating the aryl hydrocarbon receptor (21).…”

“…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.…”