Premium
Implication of myeloid differentiation factor 88 inhibitor TJ‐M2010‐5 for therapeutic intervention of hepatocellular carcinoma
Author(s) -
Liu Jing,
Zhang Xue,
Wang Haizhou,
Zhang Meng,
Peng Yanan,
Li Mingqiang,
Xie Lin,
Jiang Fengchao,
Gong Yiping,
Zhao Qiu,
Zhou Ping
Publication year - 2019
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/hepr.13359
Subject(s) - cancer research , hepatocellular carcinoma , cyclin d1 , myeloid leukemia , cyclin dependent kinase , cell cycle , kinase , chemistry , biology , apoptosis , microbiology and biotechnology , biochemistry
Aim Myeloid differentiation factor 88 (MyD88) plays a key role in tumor proliferation and metastasis. Targeting MyD88 is a potent strategy in tumor therapy. TJ‐M2010‐5 is a small molecule derivative of aminothiazole and could inhibit dimer formation of MyD88. To explore the potential of TJ‐M2010‐5 in tumor therapy, we determined its antitumor effect and correlate mechanisms of TJ‐M2010‐5 in hepatocellular carcinoma (HCC). Methods The antitumor effect of intratumoral injection of TJ‐M2010‐5 to H22 tumor‐bearing BALB/c mice was observed. Tumor growth was monitored. The expression of MyD88 and Ki‐67 were detected by immunofluorescence. In vitro , the impacts of TJ‐M2010‐5 on proliferation, cell cycle, necrosis, and apoptosis of H22 cells were evaluated. The direct and indirect effects of TJ‐M2010‐5 on macrophages were evaluated using flow cytometry. Results TJ‐M2010‐5 induced both G 0 /G 1 and G 1 /S phase arrests in HCC cells. Mechanically, downstream activation of MyD88 was suppressed by TJ‐M2010‐5 through the extracellular regulated protein kinase‐1/2/p90 ribosomal S6 kinase/glycogen synthase kinase‐3β signaling pathway. In turn, cyclin‐dependent kinase (CDK)6/cyclin D1 and CDK2/cyclin E complexes were downregulated. More importantly, TJ‐M2010‐5 significantly inhibited tumor growth in mice. Additionally, the portion of antitumor M1 macrophages (F4/80 + CD11c + ) in the tumor microenvironment were increased after TJ‐M2010‐5 treatment. Together, these data indicate that TJ‐M2010‐5 is a promising therapeutic drug for HCC. Conclusions These results indicate that MyD88 is a feasible target for antitumor treatment and TJ‐M2010‐5 is a qualified candidate for HCC therapy.