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ERK signaling pathway is involved in p15INK4b/p16INK4a expression and HepG2 growth inhibition triggered by TPA and Saikosaponin a

Oncogene volume 22, pages 955–963 (2003)Cite this article

Abstract

The signal pathway mediating induction of p15INK4b and p16INK4a during HepG2 growth inhibition triggered by the phorbol ester tumor promoter TPA (12-O-tetradecanoylphorbol 13-acetate) and the Chinese herb Saikosaponin a was investigated. Western blot of three activated forms of mitogen-activated protein kinase (MAPK) (p-ERK, p-JNK and p-p38) demonstrated that phosphorylation of ERK is dramatically induced (11.6-fold) by TPA during 15 min to 1 h and significantly induced (2.5-fold) by Saikosaponin α at 30 min, whereas phosphorylation of JNK was induced only by TPA during 30 min to 1 h. Phosphorylation of p38 was not induced by either drug. During this period, phosphorylation of one of the downstream transcriptional factors of MAPK cascade, ATF2, was 3.2- and 2.0-fold induced by TPA and Saikosaponin a, respectively, whereas that of another transcriptional factor, c-jun, was induced by TPA only. On the other hand, expressions of proto-oncogene c-jun, junB and c-fos were induced by TPA and Saikosaponin a during 30 min to 6 h of treatment. Pretreatment of 20 μg/ml PD98059, an inhibitor of MEK which is the upstream kinase of ERK, prevents the TPA- and Saikosaponin a-triggered HepG2 growth inhibition by 50 and 30%, respectively, accompanied by a 50 – 85% decrease of the p15INK4b/p16INK4a RNAs and proteins induced by both drugs. Inductions of c-fos RNA by both drugs and c-jun phosphorylation by TPA were also significantly reduced by PD98059 pretreatment. In addition, AP-1 DNA-binding assay using nonisotopic capillary electrophoresis and laser-induced fluorescence (CE/LIF) demonstrated that the AP-1-related DNA-binding activity was significantly induced by TPA and Saikosaponin a, which can be reduced by PD98059 pretreatment. These results suggested that activation of ERK together with its downstream transcriptional machinery mediated p15INK4b and p16INK4a expression that led to HepG2 growth inhibition.

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Acknowledgements

We thank TZU CHI University for the financial support and Dr Lai and Dr Hu for providing instrumentation and materials for CE/LIF analysis.

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  1. Department of Medical Technology, TZU CHI University, No. 701, Chung Yang Rd, Sec. 3, 970, Hualien, Taiwan

    Wu Wen-Sheng

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Correspondence to Wu Wen-Sheng.

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Wen-Sheng, W. ERK signaling pathway is involved in p15INK4b/p16INK4a expression and HepG2 growth inhibition triggered by TPA and Saikosaponin a. Oncogene 22, 955–963 (2003). https://doi.org/10.1038/sj.onc.1206237

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