Abstract
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.
Highlights
Albeit intensive efforts that have focused on therapeutics development, cancer is still a leading health problem worldwide [1]
Mechanistic studies revealed that ISO downregulation of XIAP and cyclin D1 protein expression accounted for its anti-cancer effects in human cancer cells [12,13]
We investigated potential cancer chemopreventive activity of this phytochemical by exploring its potential inhibitory effect on cell transformation in Cl41 cells
Summary
Albeit intensive efforts that have focused on therapeutics development, cancer is still a leading health problem worldwide [1]. Since diverse phytochemicals were reported to interfere with a specific stage of the carcinogenic process, numerous efforts have been devoted to identifying phytochemicals and phytochemical-derived agents with cancer preventive properties [4, 6,7]. ISO treatment is shown to downregulate XIAP and cyclin D1 expression by promoting transcription factor Sp1 protein degradation [12,13]. We www.impactjournals.com/oncotarget using TPA/EGF-induced mouse Cl41 cell transformation model sought to investigate the potential chemopreventive activity of ISO and molecular mechanisms underlying its activity. We found that ISO was capable of inhibiting TPA/ EGF-induced cell transformation with induction of G0/G1 cell-cycle arrest by downregulating cyclin D1 transcription via both upregulating MKP-1 expression and deactivating MKK7/JNK cascade
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