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Int J Mol Sci. 2018 Jan 23;19(2). pii: E327. doi: 10.3390/ijms19020327.

Regulation of Akt/FoxO3a/Skp2 Axis Is Critically Involved in Berberine-Induced Cell Cycle Arrest in Hepatocellular Carcinoma Cells.

Author information

1
State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. fannycpu@163.com.
2
State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. dongxiwen@fmmu.edu.cn.
3
State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. linpengxtal@126.com.
4
State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. jiangjl@fmmu.edu.cn.

Abstract

The maintenance of ordinal cell cycle phases is a critical biological process in cancer genesis, which is a crucial target for anti-cancer drugs. As an important natural isoquinoline alkaloid from Chinese herbal medicine, Berberine (BBR) has been reported to possess anti-cancer potentiality to induce cell cycle arrest in hepatocellular carcinoma cells (HCC). However, the underlying mechanism remains to be elucidated. In our present study, G0/G1 phase cell cycle arrest was observed in berberine-treated Huh-7 and HepG2 cells. Mechanically, we observed that BBR could deactivate the Akt pathway, which consequently suppressed the S-phase kinase-associated protein 2 (Skp2) expression and enhanced the expression and translocation of Forkhead box O3a (FoxO3a) into nucleus. The translocated FoxO3a on one hand could directly promote the transcription of cyclin-dependent kinase inhibitors (CDKIs) p21Cip1 and p27Kip1, on the other hand, it could repress Skp2 expression, both of which lead to up-regulation of p21Cip1 and p27Kip1, causing G0/G1 phase cell cycle arrest in HCC. In conclusion, BBR promotes the expression of CDKIs p21Cip1 and p27Kip1 via regulating the Akt/FoxO3a/Skp2 axis and further induces HCC G0/G1 phase cell cycle arrest. This research uncovered a new mechanism of an anti-cancer effect of BBR.

KEYWORDS:

Akt; FoxO3a; Skp2; berberine; hepatocellular carcinoma

PMID:
29360760
PMCID:
PMC5855549
DOI:
10.3390/ijms19020327
[Indexed for MEDLINE]
Free PMC Article

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