Isorhapontigenin (ISO) inhibited cell transformation by inducing G0/G1 phase arrest via increasing MKP-1 mRNA Stability.

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.

• Authors: Guangxun Gao, Liang Chen, Jingxia Li, Dongyun Zhang, Yong Fang, Haishan Huang, Xiequn Chen, Chuanshu Huang
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 9 Pg. 2664-77 (May 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24797581 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Stilbenes
• isorhapontigenin
• Cyclin D1
• Luciferases
• Dual Specificity Phosphatase 1
• Dusp1 protein, mouse

Topics

• Animals
• Blotting, Western
• Cell Adhesion (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Cell Transformation, Neoplastic (drug effects, pathology)
• Cells, Cultured
• Cyclin D1 (genetics, metabolism)
• Dual Specificity Phosphatase 1 (genetics, metabolism)
• Epidermis (drug effects, metabolism, pathology)
• Flow Cytometry
• G1 Phase (drug effects)
• Luciferases (metabolism)
• Mice
• Phosphorylation (drug effects)
• RNA Stability (drug effects, genetics)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Resting Phase, Cell Cycle (drug effects)
• Reverse Transcriptase Polymerase Chain Reaction
• Stilbenes (pharmacology)