title: Anti-cancer drug 3,3'-diindolylmethane activates Wnt4 signaling to enhance gastric cancer cell stemness and tumorigenesis.
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.
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.|Department of Clinical Laboratory, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan, P. R. China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Gong
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Fu
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.
authors.forename: Yaoxiang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.
authors.forename: Zhaoji
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Qian
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China.
authors.forename: Wenrong
authors.initials: W
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D063646:Carcinogenesis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000009:adverse effects*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000473:pathology*; D060528:Wnt4 Protein / Q000187:drug effects / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C512018:1,1-bis(3'-indolyl)methane; D000970:Antineoplastic Agents; D007211:Indoles; C555581:WNT4 protein, human; D060528:Wnt4 Protein
keywords: 3,3′-diindolylmethane; Wnt4; gastric cancer; stemness; tumorigenesis; β-catenin