Caudatin induces cell apoptosis in gastric cancer cells through modulation of Wnt/β-catenin signaling

Abstract

Abstract. Caudatin has been reported to trigger apoptosis in several types of cancer cell lines. In the present study, we investigated whether caudatin has therapeutic value in gastric cancer and examined the effects of caudatin on the expression of β-catenin in human gastric carcinoma cell lines. Here, we showed that caudatin treatment resulted in a dose-and time-dependent inhibition of proliferation of the gastric carcinoma cell lines. Cell cycle analysis demonstrated that caudatin induced G0/G1 arrest and downregulated CDK2 levels. In contrast, the expression of the p21 protein was increased. AGS cells treated with caudatin exhibited typical characteristics of apoptosis, which were accompanied by activation of caspase-3, -8, -9 and PARP. Western blot analysis and immunocytochemical staining showed that caudatin induced a reduction in β-catenin expression and this reduction was due to proteosome-mediated degradation. This reduction in β-catenin activation was due to the downregulation of its downstream targets cyclinD1 and c-MYC in all gastric carcinoma cell lines. Furthermore, we demonstrated that gastric adenocarcinoma tissues and AGS cells exhibited abnormal expression of miR-372. Additionally, caudatin downregulated the expression of oncomir miR-372 and miR-21, and upregulated tumor suppressor let-7a miRNA expression. These data revealed that inhibition of Wnt/β-catenin signaling is a novel mechanism of action for caudatin during therapeutic intervention in gastric cancers. IntroductionGastric cancer is one of the most common malignancies and the second leading cause of cancer-related mortality worldwide.Surgery and systemic treatment regimens in combination with radiotherapy and chemotherapy are able to cure this malignancy in the majority of cases. Unfortunately, the young age of typical gastric cancer patients further enhances the time at risk for the side effects of these therapies. Delayed toxicity and the development of secondary malignancies are a serious concern for the current anti-neoplastic armamentarium (1,2). Therefore, it is urgent to further characterize the entity of gastric tumors to better understand and predict their biological behaviors and to identify novel high efficient and low toxic therapeutic agents for the treatment of gastric cancer in clinical practice (3).Modern pharmacologic study proves that C-21 steroidal glycosides are important biological active compounds, which are widely found in the plants of the Asclepiadaceae family and exhibit extensive pharmacological effects such as inhibition of proliferation, induction of apoptosis and inhibition of the invasion of tumor cells (4,5). Caudatin, a C-21 steroidal glycoside, is mainly isolated from the root of Cynanchum bungei Decne in China. Recent studies demonstrated that caudatin induced the apoptosis of HepG2 cells or the SMMC772 cell line (6,7). Wang et al (8) found that caudatin had an inhibitory activity on the secretion of HBsAg and HBV DNA replication. Furthermore, caudatin as a prospective anti-HCC drug with the mechanism...

USP39 promotes colorectal cancer growth and metastasis through the Wnt/β-catenin pathway

“…β-catenin which is the key molecule in this pathway, is a multifunctional protein (19), and acts as a key transcriptional factor in the Wnt pathway. It widely participates in the regulation of cell proliferation and migration (20,21). In the present study, we observed a significant effect of USP39 knockdown on β-catenin levels, consistent with reduced growth and migration.…”

Caudatin targets TNFAIP1/NF-κB and cytochrome c/caspase signaling to suppress tumor progression in human uterine cancer

“…Caudatin, a C-21 steroidal glycoside, is mainly isolated from the traditional Chinese medicine 'baishouwu', which was the root tuber of Cynanchum auriculatum Royle ex Wight. It has been reported that the antitumor effect of caudatin has been shown to exhibit anti-proliferation effects against cancer cells of different origins, including glioblastoma, lung, gastric, and liver cancer (12)(13)(14)(15)(16). In our previous studies, caudatin induced apoptosis of AGS cells or the HGC-27 cell line (14).…”

“…It has been reported that the antitumor effect of caudatin has been shown to exhibit anti-proliferation effects against cancer cells of different origins, including glioblastoma, lung, gastric, and liver cancer (12)(13)(14)(15)(16). In our previous studies, caudatin induced apoptosis of AGS cells or the HGC-27 cell line (14). Wang et al found that caudatin had an inhibitory activity on the secretion of HBsAg and HBV DNA replication (17).…”

“…Caudatin is known to induce apoptosis in variety of cancer cells, which is considered to be an important mechanism for their antitumor activity and prevention of carcinogenesis (13,14). Annexin V-FITC/PI double-labeled flow cytometry was used to assess the ratio of apoptotic HeLa cells following caudatin treatment.…”

Determination of Caudatin in Rat Plasma by UPLC-MS/MS: Application to a Preclinical Pharmacokinetic Study

“…1 ) is mainly isolated from the root of Cynanchum bungei Decne , a traditional Chinese medicine and health food, which has potent anti-hepatitis B virus (HBV) activity [3,4] . Moreover, many lines of evidence have shown that caudatin induced apoptosis of many cancer cells [5][6][7][8][9] .Currently, several analytical methods exist for quantifying caudatin in the plants and biological samples by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) [10][11][12] . Quantification and pharmacokinetics studies on constituents of Traditional Chinese Medicine in plasma are required to offer suitable references in clinical application.…”