Effects of CS-1 on A431 cell proliferation, cell cycle, and epidermal growth factor receptor signal transduction

• Published in: Acta biochimica et biophysica Sinica Vol. 44; no. 2; pp. 136 - 146
• Main Authors: Du, Haiyan, Xu, Bo, Wu, Caixia, Li, Min, Ran, Fuxiang, Cai, Shaoqing, Cui, Jingrong
• Format: Journal Article
• Language: English
• Published: China Oxford University Press 01.02.2012
• Subjects: Alkaloids - isolation & purification; Alkaloids - pharmacology; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; CS-1; Cyclin D1 - metabolism; Drugs, Chinese Herbal - isolation & purification; Drugs, Chinese Herbal - pharmacology; Humans; MAP Kinase Signaling System - drug effects; Medicine, Chinese Traditional; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction - drug effects; STAT3 Transcription Factor - metabolism; 丝裂原活化蛋白激酶; 信号转导; 细胞周期停滞; 细胞周期蛋白D1; 细胞增殖; 细胞外信号调节激酶; 表皮生长因子受体; EGFR signaling pathway; high content screening; CS-1; cell cycle
• ISSN: 1672-9145; 1745-7270
• DOI: 10.1093/abbs/gmr111

CS-1, a new alkaloid with a molecular formula of C21H2oOsN2S, is extracted from traditional Chinese medi- cine. Previous studies have shown that CS-1 can inhibit the proliferation of several human carcinoma cells in vivo and in vitro. The aims of this study are to investigate the anti-tumor effect and mechanism of CS-1 in epidermal growth factor receptor （EGFR） signaling pathway in human A431 cell line. Through the sulforhodamine B assay, we found that CS-1 inhibited A431 cell prolifer- ation in the concentration- and time-dependent manners. The inhibitory rate ranged from 14.5% to 87.8% after 24 h of incubation. High content screening （HCS） multi- parameters cytotoxicity analysis showed that CS-1 at high concentration had slight cytotoxicity that resulted from the cell permeabilization and slight reduction in total mitochondrial mass, whereas no change in nucleus size/ morphology and lysosomal mass-pH was found. The cyto- toxicity of CS-1 was not a major reason for its anti- proliferative effect. Cell cycle analysis indicated that CS-1 induced Gl-phase arrest in A431 cells in a time- dependent manner at high concentration （2.5 ttM）, and S-phase arrest at low concentration （0.625 ttM）. The HCS assay also showed that CS-1 could inhibit the EGFR in- ternalization, extracellular-signal-regulated kinase （Erk）/ mitogen-activated protein kinase translocation to nucleus, the accumulation of phosphorylated protein kinase B （Akt）, signal transducer and activator of transcription 3 （STAT3）, and cyclin D1 in the nucleus. These results were confirmed by the western blot analysis. CS-I might inhibit the epidermal growth factor binding to its recep- tor, resulting in the inhibition of the accumulation of phosphorylated Erk and Akt, and STAT3 in the nucleus, and affecting the transcription of cyclin D1 and cell cycle arrest in G1/S phase.