title: The matricellular protein CCN1 suppresses lung cancer cell growth by inducing senescence via the p53/p21 pathway.
abstract: CCN1, a secreted matrix-associated molecule, is involved in multiple cellular processes. Previous studies have indicated that expression of CCN1 correlates inversely with the aggressiveness of non-small-cell lung carcinoma (NSCLC); however, the underlying mechanisms remain elusive. Using three NSCLC cell line systems, here we show that long-term treatment of cells with the recombinant CCN1 protein led to a permanent cell cycle arrest in G1 phase; cells remained viable as judged by apoptotic assays. CCN1-treated NSCLC cells acquired a phenotype characteristic of senescent cells, including an enlarged and flattened cell shape and expression of the senescence-associated β-galactosidase. Immunoblot analysis showed that addition of CCN1 increased the abundance of hypo-phosphorylated Rb, as well as accumulation of p53 and p21. Silencing the expression of p53 or p21 by lentivirus-mediated shRNA production in cells blocked the CCN1-induced senescence. Furthermore, a CCN1 mutant defective for binding integrin α6β1 and co-receptor heparan sulfate proteoglycans was incapable of senescence induction. Our finding that direct addition of CCN1 induces senescence in NSCLC cells provides a potential novel strategy for therapeutic intervention of lung cancers.
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, 112, Taiwan. sjleu@ym.edu.tw
authors.forename: Shr-Jeng
authors.initials: SJ
authors.lastname: Jim Leu
authors.forename: Jung-Sung
authors.initials: JS
authors.lastname: Sung
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Chen
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Chen
authors.forename: Jian-Yu
authors.initials: JY
authors.lastname: Cheng
authors.forename: Tse-Yen
authors.initials: TY
authors.lastname: Wang
authors.forename: Jeng-Jung
authors.initials: JJ
authors.lastname: Wang
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D055515:Cysteine-Rich Protein 61 / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D055515:Cysteine-Rich Protein 61
keywords: CCN1; LUNG CANCER; SENESCENCE; p21; p53