Journal
CANCER LETTERS
Volume 322, Issue 2, Pages 185-194Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2012.03.004
Keywords
Lung cancer; Gambogenic acid; G1 arrest; Cyclin D1; GSK3 beta; Autophagy
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Funding
- National Key Program for Basic Research [2010CB529201, 2012CB910800]
- National Natural Science Foundation [81071930, 81171925]
- Special Foundation of President
- Chinese Academy of Sciences [KSCX1-YW-R-26, KSCX2-YW-R-235]
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Cyclin D1, an oncogenic Cl cyclin which can be induced by environmental carcinogens and whose overexpression may cause dysplasia and carcinoma, has been shown to be a target for cancer chemoprevention and therapy. In this study, we investigated the effects and underlying mechanisms of action of a polyprenylated xanthone, gambogenic acid (GEA) on gefitinib-sensitive and -resistant lung cancer cells. We found that GEA inhibited proliferation, caused G1 arrest and repressed colony-forming activity of lung cancer cells. GEA induced degradation of cyclin D1 via the proteasome pathway, and triggered dephosphorylation of GSK3 beta which was required for cyclin D1 turnover, because GSK3 beta inactivation by its inhibitor or specific siRNA markedly attenuated GEA-caused cyclin D1 catabolism. GEA induced autophagy of lung cancer cells, possibly due to activation of GSK3 beta and inactivation of AKT/mTOR signal pathway. These results indicate that GEA is a cyclin D1 inhibitor and a GSK3 beta activator which may have chemopreventive and therapeutic potential for lung cancer. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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