The matricellular protein CCN1 suppresses lung cancer cell growth by inducing senescence via the p53/p21 pathway

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...

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Published in:Journal of cellular biochemistry 2013-09, Vol.114 (9), p.2082-2093
Main Authors: Jim Leu, Shr-Jeng, Sung, Jung-Sung, Chen, Mei-Yu, Chen, Chih-Wei, Cheng, Jian-Yu, Wang, Tse-Yen, Wang, Jeng-Jung
Format: Article
Language:English
Subjects:
Blotting, Western
CCN1
Cell Cycle - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Cellular Senescence - drug effects
Cyclin-Dependent Kinase Inhibitor p21
Cysteine-Rich Protein 61 - pharmacology
Humans
LUNG CANCER
Lung Neoplasms - metabolism
p21
p53
SENESCENCE
Signal Transduction - drug effects
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Summary: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. J. Cell. Biochem. 114: 2082–2093, 2013. © 2013 Wiley Periodicals, Inc.
ISSN:0730-2312
1097-4644
DOI:10.1002/jcb.24557