caudatin and Carcinoma

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.

Topics: Apoptosis; beta Catenin; Carcinoma; Cell Cycle Checkpoints; Cell Death; Cell Line, Tumor; Cell Proliferation; G1 Phase; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Glycosides; Humans; MicroRNAs; Proteasome Endopeptidase Complex; Resting Phase, Cell Cycle; Signal Transduction; Steroids; Stomach Neoplasms; Up-Regulation; Wnt Proteins

In this study, we investigate the anti-cancer activity of caudatin in carcinomic human alveolar basal epithelial cell line A549 and anti-angiogenic activity in human umbilical vein endothelial cells (HUVECs). We show that caudatin impairs the cell viability and induces G(0) /G(1) phase arrest in A549 cells with a dose dependent manner. A549 cells, not HUVECs, dealing with caudatin exhibited typical characteristics of apoptosis, which were accompanied by activation of caspase-3, caspase-9 and Poly(ADP-Ribose) Polymerase (PARP). In addition, caudatin treatment resulted in a decrease of β-catenin and increase of phosphorylation of β-catenin, and inhibited phosphorylation levels of GSK3β (Ser 9) in A549 cells. Conditional medium of A549 cells-induced or growth factors-induced tube formation of HUVECs was markedly inhibited by caudatin treatment, which was associated with the inhibiting VEGF secretion from A549 cells by caudatin. Our findings suggest that caudatin inhibits carcinomic human alveolar basal epithelial cell growth and angiogenesis by targeting GSK3β/β-catenin pathway and suppressing VEGF production.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; beta Catenin; Carcinoma; Caspase 3; Caspase 9; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Culture Media, Conditioned; Dose-Response Relationship, Drug; Epithelial Cells; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Glycosides; Human Umbilical Vein Endothelial Cells; Humans; Lung Neoplasms; Neovascularization, Pathologic; Organ Specificity; Poly(ADP-ribose) Polymerases; Signal Transduction; Steroids; Vascular Endothelial Growth Factor A