Anti-cancer drug 3,3'-diindolylmethane activates Wnt4 signaling to enhance gastric cancer cell stemness and tumorigenesis.

Yanhua Zhu,Hui Shi,Fei Mao,Hailong Fu,Zhaoji Pan,Lijun Wu,Hui Qian,Bin Zhang,Wei Zhu,Wenrong Xu,Yaoxiang Sun,Xu Zhang,Aihua Gong

doi:10.18632/oncotarget.7684

Abstract

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.

Highlights

Gastric cancer is one of the most lethal cancers in Asia and the second leading cause of cancer-related death worldwide [1,2,3]
We found that low level of DIM (1 μM and 10 μM) could obviously promote gastric cancer cell proliferation, migration, and stemness through the activation of autocrine Wnt4/β-catenin signaling
Low level of DIM promotes the proliferation and migration of gastric cancer cells To determine the effects of various levels of DIM on human gastric cancer cell growth, we analyzed the colony formation abilities of six gastric cancer cell lines which were treated with different concentrations of DIM for 10 days

Summary

Introduction

Gastric cancer is one of the most lethal cancers in Asia and the second leading cause of cancer-related death worldwide [1,2,3]. Chemotherapy is one of the primary treatments for gastric cancer. The main reason is that gastric cancer cells can develop multidrug resistance to chemotherapeutic drugs, which significantly limits the application of chemotherapy drugs [4, 5]. Many studies have shown that DIM has anticancer effects in various cancer cells in vitro and in vivo. DIM inhibits cell proliferation and induces cell apoptosis in cancer cells [7, 16,17,18]. Low level of DIM could activate estrogen receptor α and induce the proliferation of breast cancer cells in the absence of estradiol [21]. The above mentioned studies indicate that DIM at certain doses could effectively inhibit cancer progression. The effects of low level of DIM on cancer remain largely unknown

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Results

Conclusion