Document Type

Journal Article

Department/Unit

School of Chinese Medicine

Title

Gambogenic acid induces G1 arrest via GSK3β-dependent cyclin D1 degradation and triggers autophagy in lung cancer cells

Language

English

Abstract

Cyclin D1, an oncogenic G1 cyclin which can be induced by environmental carcinogens and whose over-expression 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 GSK3β which was required for cyclin D1 turnover, because GSK3β 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 GSK3β and inactivation of AKT/mTOR signal pathway. These results indicate that GEA is a cyclin D1 inhibitor and a GSK3β activator which may have chemopreventive and therapeutic potential for lung cancer.

Keywords

Lung cancer, Gambogenic acid, G1 arrest, Cyclin D1, GSK3β, Autophagy

Publication Date

2012

Source Publication Title

Cancer Letters

Volume

322

Issue

2

Start Page

185

End Page

194

Publisher

Elsevier

Peer Reviewed

1

Funder

This work was supported in part by the National Key Program for Basic Research (2010CB529201 and 2012CB910800), the National Natural Science Foundation (81071930 and 81171925), the Special Foundation of President and the Key Project of Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX1-YW-R-26 and KSCX2-YW-R-235).

DOI

10.1016/j.canlet.2012.03.004

Link to Publisher's Edition

http://dx.doi.org/10.1016/j.canlet.2012.03.004

ISSN (print)

03043835

ISSN (electronic)

18727980

ESSN

18727980

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