3,3′-diindolylmethane exerts antiproliferation and apoptosis induction by TRAF2-p38 axis in gastric cancer

Abstract

3,3′-diindolylmethane (DIM), an active phytochemical derivative extracted from cruciferous vegetables, possesses anticancer effects. However, the underlying anticancer mechanism of DIM in gastric cancer remains unknown. Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2), one of the signal transduction proteins, plays critical role in proliferation and apoptosis of human gastric cancer cells, but there are still lack of practical pharmacological modulators for potential clinical application. Here, we further explored the role of TRAF2 in inhibiting cell proliferation and inducing apoptosis by DIM in human gastric cancer BGC-823 and SGC-7901 cells. After treating BGC-823 and SGC-7901 cells with DIM for 24 h, cell proliferation, apoptosis and TRAF2-related protein were measured. Our findings showed that DIM inhibited the expressions of TRAF2, activated p-p38 and its downstream protein p-p53, which were paralleled with DIM-triggered cells proliferation, inhibition and apoptosis induction. These effects of DIM were reversed by TRAF2 overexpression or p38 mitogen-activated protein kinase (MAPK)-specific inhibitor (SB203580). Taken together, our data suggest that regulating TRAF2/p38 MAPK signaling pathway is essential for inhibiting gastric cancer proliferation and inducing apoptosis by DIM. These findings broaden the understanding of the pharmacological mechanism of DIM’s action as a new modulator of TRAF2, and provide a new therapeutic target for human gastric cancer.

3,3’-Diindolylmethane induces apoptosis and autophagy in fission yeast

“…Similar to the results in human studies [6,57], we found that DIM induces autophagy in fission yeast (Fig. 4B) when we used the low concentration of DIM ( 5μg/ml).…”

“…Recent studies in humans show that DIM is a potential anti-cancer drug that acts by the induction of apoptosis in a wide range of cancer types including the breast [11,12,52,56], prostate [16], gastric [57], pancreatic [58], and hepatoma [13].…”

“…DIM also induces autophagy that substantially suppresses tumor growth and causes cancer cell death [57,[59][60][61]. However, the mechanisms of autophagy and apoptosis induction by DIM in humans are not fully understood.…”

3,3’-Diindolylmethane induces apoptosis and autophagy in fission yeast

“…Recent studies in humans show that DIM is a potential anti-cancer drug that acts by the induction of apoptosis in a wide range of cancer types including the breast [11,12,52,57], prostate [16], gastric [58], pancreatic [59], and hepatoma [13]. DIM also induces autophagy that substantially suppresses tumor growth and causes cancer cell death [58,[60][61][62]. However, the mechanisms of autophagy and apoptosis induction by DIM in humans are not fully understood.…”

Evaluation of Synthetic 2,4-Disubstituted-benzo[g]quinoxaline Derivatives as Potential Anticancer Agents

“…Furthermore, the pro-apoptotic protein Bax and the ant-apoptotic protein Bcl2 are signs of apoptosis induction, which may be useful targets in the mitochondrial-dependent pathway of apoptosis [ 11 , 12 ]. Therefore, apoptosis induction in cancer cells can be used as a new weapon against cancer cell proliferation [ 13 , 14 ].…”