title: Effects of CS-1 on A431 cell proliferation, cell cycle, and epidermal growth factor receptor signal transduction.
abstract: CS-1, a new alkaloid with a molecular formula of C(21)H(20)O(8)N(2)S, is extracted from traditional Chinese medicine. 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 proliferation 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 cytotoxicity of CS-1 was not a major reason for its anti-proliferative effect. Cell cycle analysis indicated that CS-1 induced G1-phase arrest in A431 cells in a time-dependent manner at high concentration (2.5 μM), and S-phase arrest at low concentration (0.625 μM). The HCS assay also showed that CS-1 could inhibit the EGFR internalization, 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-1 might inhibit the epidermal growth factor binding to its receptor, 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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Du
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.forename: Caixia
authors.initials: C
authors.lastname: Wu
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Fuxiang
authors.initials: F
authors.lastname: Ran
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Cai
authors.forename: Jingrong
authors.initials: J
authors.lastname: Cui
mesh_terms: D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008516:Medicine, Chinese Traditional; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; C530104:CCND1 protein, human; D004365:Drugs, Chinese Herbal; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019938:Cyclin D1; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt