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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies throughout the world, with a high incidence in the Asian population
These results indicated that these two different HCC cell lines responded differently to BBR-induced cytotoxicity, with inhibition of cell growth in a dose- and time-dependent manner
We found that BBR could induce time- and dose-dependent inhibition of the proliferation of Huh-7 and HepG2 cells
Summary
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies throughout the world, with a high incidence in the Asian population. BBR has been reported to possess anti-tumor activity in multiple types of cancers including HCC [10,11]. To the best of our knowledge, few studies have demonstrated, in detail, the underlying mechanism by which BBR could influence HCC cell cycle, a critical cellular activity concerning cancer cell proliferation and neoplastic transformation. Many studies have demonstrated that FoxO3a exerts tumor suppressive activities by negatively regulating cell proliferation, promoting cell cycle arrest, repairing damaged DNA and inducing cell apoptosis after translocating into nucleus [14]. To investigate the mechanism by which BBR influences HCC cell cycle, we carried out the research to discover potential relationships among FoxO3a, Skp and CKDIs. The consequent findings can provide new insights on how BBR inhibits tumor proliferation and exerts anti-cancer activity
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