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Tetrandrine inhibits Wnt/?-catenin signaling and suppresses tumor growth of human colorectal cancer.

ABSTRACT: As one of the most common malignancies, colon cancer is initiated by abnormal activation of the Wnt/?-catenin pathway. Although the treatment options have increased for some patients, overall progress has been modest. Thus, there is a great need to develop new treatments. We have found that bisbenzylisoquinoline alkaloid tetrandrine (TET) exhibits anticancer activity. TET is used as a calcium channel blocker to treat hypertensive and arrhythmic conditions in Chinese medicine. Here, we investigate the molecular basis underlying TET's anticancer activity. We compare TET with six chemotherapy drugs in eight cancer lines and find that TET exhibits comparable anticancer activities with camptothecin, vincristine, paclitaxel, and doxorubicin, and better than that of 5-fluorouracil (5-FU) and carboplatin. TET IC?? is ?5 ?M in most of the tested cancer lines. TET exhibits synergistic anticancer activity with 5-FU and reduces migration and invasion capabilities of HCT116 cells. Furthermore, TET induces apoptosis and inhibits xenograft tumor growth of colon cancer. TET treatment leads to a decrease in ?-catenin protein level in xenograft tumors, which is confirmed by T-cell factor/lymphocyte enhancer factor and c-Myc reporter assays. It is noteworthy that HCT116 cells with allelic oncogenic ?-catenin deleted are less sensitive to TET-mediated inhibition of proliferation, viability, and xenograft tumor growth. Thus, our findings strongly suggest that the anticancer effect of TET in colon cancer may be at least in part mediated by targeting ?-catenin activity. Therefore, TET may be used alone or in combination as an effective anticancer agent.

SUBMITTER: He BC

PROVIDER: S-EPMC3033706 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Tetrandrine inhibits Wnt/β-catenin signaling and suppresses tumor growth of human colorectal cancer.

He Bai-Cheng BC Gao Jian-Li JL Zhang Bing-Qiang BQ Luo Qing Q Shi Qiong Q Kim Stephanie H SH Huang Enyi E Gao Yanhong Y Yang Ke K Wagner Eric R ER Wang Linyuan L Tang Ni N Luo Jinyong J Liu Xing X Li Mi M Bi Yang Y Shen Jikun J Luther Gaurav G Hu Ning N Zhou Qixin Q Luu Hue H HH Haydon Rex C RC Zhao Yingming Y He Tong-Chuan TC

Molecular pharmacology 20101026 2

As one of the most common malignancies, colon cancer is initiated by abnormal activation of the Wnt/β-catenin pathway. Although the treatment options have increased for some patients, overall progress has been modest. Thus, there is a great need to develop new treatments. We have found that bisbenzylisoquinoline alkaloid tetrandrine (TET) exhibits anticancer activity. TET is used as a calcium channel blocker to treat hypertensive and arrhythmic conditions in Chinese medicine. Here, we investigat ...[more]

PMID: 20978119

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Project description:BACKGROUND:Gastric cancer is one of the most common malignant tumors. Cyclin G2 has been shown to be associated with the development of multiple types of tumors, but its underlying mechanisms in gastric tumors is not well-understood. The aim of this study is to investigate the role and the underlying mechanisms of cyclin G2 on Wnt/?-catenin signaling in gastric cancer. METHODS:Real-time PCR, immunohistochemistry and in silico assay were used to determine the expression of cyclin G2 in gastric cancer. TCGA datasets were used to evaluate the association between cyclin G2 expression and the prognostic landscape of gastric cancers. The effects of ectopic and endogenous cyclin G2 on the proliferation and migration of gastric cancer cells were assessed using the MTS assay, colony formation assay, cell cycle assay, wound healing assay and transwell assay. Moreover, a xenograft model and a metastasis model of nude mice was used to determine the influence of cyclin G2 on gastric tumor growth and migration in vivo. The effects of cyclin G2 expression on Wnt/?-catenin signaling were explored using a TOPFlash luciferase reporter assay, and the molecular mechanisms involved were investigated using immunoblots assay, yeast two-hybrid screening, immunoprecipitation and Duolink in situ PLA. Ccng2-/- mice were generated to further confirm the inhibitory effect of cyclin G2 on Wnt/?-catenin signaling in vivo. Furthermore, GSK-3? inhibitors were utilized to explore the role of Wnt/?-catenin signaling in the suppression effect of cyclin G2 on gastric cancer cell proliferation and migration. RESULTS:We found that cyclin G2 levels were decreased in gastric cancer tissues and were associated with tumor size, migration and poor differentiation status. Moreover, overexpression of cyclin G2 attenuated tumor growth and metastasis both in vitro and in vivo. Dpr1 was identified as a cyclin G2-interacting protein which was required for the cyclin G2-mediated inhibition of ?-catenin expression. Mechanically, cyclin G2 impacted the activity of CKI to phosphorylate Dpr1, which has been proved to be a protein that acts as a suppressor of Wnt/?-catenin signaling when unphosphorylated. Furthermore, GSK-3? inhibitors abolished the cyclin G2-induced suppression of cell proliferation and migration. CONCLUSIONS:This study demonstrates that cyclin G2 suppresses Wnt/?-catenin signaling and inhibits gastric cancer cell growth and migration through Dapper1.

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Tetrandrine inhibits Wnt/?-catenin signaling and suppresses tumor growth of human colorectal cancer.

Publications

Tetrandrine inhibits Wnt/β-catenin signaling and suppresses tumor growth of human colorectal cancer.

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