title: Caffeic acid 3,4-dihydroxy-phenethyl ester induces cancer cell senescence by suppressing twist expression.
abstract: Compared with traditional cytotoxic cancer therapy, therapy-induced cancer cell senescence attracts much interest because it is similarly effective, has fewer side effects, and is more efficiently cleared by immune cells. In this study, we demonstrate that unlike caffeic acid phenethyl ester, caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE), which is isolated from the medicinal plants Sarcandra glabra and Teucrium pilosum, inhibits human cancer cell growth and colony formation by inducing cancer cell senescence, not apoptosis. CADPE induces cell senescence and morphology changes by increasing cellular size and cytoplasmic granularity, enhancing senescence-associated β-galactosidase activity and differentiated embryo-chondrocyte expressed gene 1 expression, and blocking cell-cycle arrest in the G(1) phase. To help understand the underlying mechanisms, we show that CADPE significantly suppressed the expression of Twist1 and led to the up-regulation of rat sarcoma, p53, p21(WAF1/CIP1), and p16(INK4a) proteins in a dose-dependent manner, resulting in the hypophosphorylation of retinoblastoma protein. Furthermore, overexpression of Twist1 prevented CADPE-induced cell senescence in tumor cells. Therefore, our studies provide evidence for a novel role of CADPE in cancer cell senescence by targeting the Twist1-dependent senescence signaling pathway.
authors.affiliation: Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Anliang
authors.initials: A
authors.lastname: Dong
authors.forename: Yuanzhang
authors.initials: Y
authors.lastname: Fang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Xie
authors.forename: Xian
authors.initials: X
authors.lastname: Wu
authors.forename: Lipeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Lian
authors.forename: Yihua
authors.initials: Y
authors.lastname: Chen
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D017304:Annexin A5; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002109:Caffeic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D051879:Twist-Related Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D002109:Caffeic Acids; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; D051879:Twist-Related Protein 1; C548196:caffeic acid 3,4-dihydroxyphenethyl ester; D001616:beta-Galactosidase