Anti-cancer drug 3,3′-diindolylmethane activates Wnt4 signaling to enhance gastric cancer cell stemness and tumorigenesis
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Yanhua Zhu1,2,*, Bin Zhang1,*, Aihua Gong1, Hailong Fu1, Xu Zhang1, Hui Shi1, Yaoxiang Sun1, Lijun Wu1, Zhaoji Pan1, Fei Mao1, Wei Zhu1, Hui Qian1 and Wenrong Xu1
1 Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China
2 Department of Clinical Laboratory, Dali Bai Autonomous Prefecture People’s Hospital, Dali, Yunnan, P. R. China
* These authors have contributed equally to this work
Wenrong Xu, email:
Hui Qian, email:
Keywords: 3,3′-diindolylmethane, gastric cancer, Wnt4, β-catenin, stemness, tumorigenesis
Received: June 01, 2015 Accepted: February 05, 2016 Published: February 24, 2016
As a natural health supplement, 3,3′-diindolylmethane (DIM) is proposed as a preventive and chemotherapeutic agent for cancer by inhibiting cell proliferation and inducing cell apoptosis. However, we found that in contrary to high level of DIM (30 μM), low level of DIM (1 μM and 10 μM) obviously promoted gastric cancer cell growth and migration. In addition, we found that low level of DIM increased the expression of stemness factors and enhanced the pluripotency of gastric cancer cells. Low level of DIM promoted gastric cancer progression by inducing the PORCN-dependent secretion of Wnt4 and the activation of β-catenin signaling. Wnt4 knockdown reversed the effects of low level of DIM on gastric cancer cells. The results of in vivo studies showed that gastric cancer cells treated with low level of DIM (1 μM) grew faster and expressed higher level of Wnt4 than control cells. Taken together, our findings indicate that low level of DIM activates autocrine Wnt4 signaling to enhance the progression of gastric cancer, which may suggest an adverse aspect of DIM in cancer therapy. Our findings will provide a new aspect for the safety of DIM in its clinical application.
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