Isorhapontigenin (ISO) inhibited cell transformation by inducing G0/G1 phase arrest via increasing MKP-1 mRNA stability
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Guangxun Gao1,2,*, Liang Chen1,*, Jingxia Li1, Dongyun Zhang1,Yong Fang1, Haishan Huang1, Xiequn Chen2, and Chuanshu Huang1,*
1 Nelson Institute of Environmental Medicine, New York University School of Medicine,Tuxedo, NY, USA
2 Department of Hematology, Xijing Hospital, Fourth Military Medical University,Xi’an, Shaanxi, China
* These authors contributed equally to this work
Chuanshu Huang, email:
Keywords: Isorhapontigenin; MKP-1; Transformation; Chemoprevention; Cyclin D1
Received: February 18, 2014 Accepted: March 26 , 2014 Published: March 26, 2014
The cancer chemopreventive property of Chinese herb new isolate isorhapontigenin (ISO) and mechanisms underlying its activity have never been explored. Here we demonstrated that ISO treatment with various concentrations for 3 weeks could dramatically inhibit TPA/EGF-induced cell transformation of Cl41 cells in Soft Agar assay, whereas co-incubation of cells with ISO at the same concentrations could elicit G0/G1 cell-cycle arrest without redundant cytotoxic effects on non-transformed cells. Further studies showed that ISO treatment resulted in cyclin D1 downregulation in dose- and time-dependent manner. Our results indicated that ISO regulated cyclin D1 at transcription level via targeting JNK/C-Jun/AP-1 activation. Moreover, we found that ISO-inhibited JNK/C-Jun/AP-1 activation was mediated by both upregulation of MKP-1 expression through increasing its mRNA stability and deactivating MKK7. Most importantly, MKP-1 knockdown could attenuate ISO-mediated suppression of JNK/C-Jun activation and cyclin D1 expression, as well as G0/G1 cell cycle arrest and cell transformation inhibition, while ectopic expression of FLAG-cyclin D1 T286A mutant also reversed ISO-induced G0/G1 cell-cycle arrest and inhibition of cell transformation. Our results demonstrated that ISO is a promising chemopreventive agent via upregulating mkp-1 mRNA stability, which is distinct from its cancer therapeutic effect with downregulation of XIAP and cyclin D1 expression.
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