Berberine Suppresses Cyclin D1 Expression through Proteasomal Degradation in Human Hepatoma Cells

Abstract

The aim of this study is to explore the underlying mechanism on berberine-induced Cyclin D1 degradation in human hepatic carcinoma. We observed that berberine could suppress both in vitro and in vivo expression of Cyclin D1 in hepatoma cells. Berberine exhibits dose- and time-dependent inhibition on Cyclin D1 expression in human hepatoma cell HepG2. Berberine increases the phosphorylation of Cyclin D1 at Thr286 site and potentiates Cyclin D1 nuclear export to cytoplasm for proteasomal degradation. In addition, berberine recruits the Skp, Cullin, F-box containing complex-β-Transducin Repeat Containing Protein (SCFβ-TrCP) complex to facilitate Cyclin D1 ubiquitin-proteasome dependent proteolysis. Knockdown of β-TrCP blocks Cyclin D1 turnover induced by berberine; blocking the protein degradation induced by berberine in HepG2 cells increases tumor cell resistance to berberine. Our results shed light on berberine′s potential as an anti-tumor agent for clinical cancer therapy.

F‑box proteins involved in cancer‑associated drug resistance (Review)

“…Berberine promotes the phosphorylation of cyclin D1 at the T286 site and then accelerates binding of β-TrCP to cyclin D1 thus mediating its degradation. It was thus apparent that knockdown of β-TrCP expression could reduce this phenomenon (81). On the other hand, Nrf2 is a newly identified substrate of β-TrCP (82).…”

What Chinese Medicine Can Do for Liver Cancer?

“…Also, cyclin D1 overexpression is mainly responsible for tumor expansion, metastasis as well as angiogenesis. Berberine was found to repress the expression of cyclin D1 via proteasomal degradation in HCC [11]. In addition, our group identified that berberine exerted antimigratory and anti-invasive abilities in HCC cells involving the upregulation of PAI-1 and downregulation of uPA [12].…”

<p>The Anti-Cancer Mechanisms of Berberine: A Review</p>

“…19,20 Studies showed that BBR regulated cell cycle and inhibited cell proliferation in multiple cancers. 6,21,22 BBR induced G1 phase cycle arrest in A549 lung cancer cells through inhibition of the expression of Cyclin D1 and Cyclin E1. 21 In addition, a combination of an Hsp90 inhibitor and BBR inhibited cell growth via inhibition of CDK4 expression and modulation of cyclin D1 in colorectal cancer cells.…”

“…22 In HepG2 human hepatoma cells, BBR suppressed cyclin D1 expression in vitro and in vivo. 6 Furthermore, BBR arrested the cell cycle at G1 via reduced expression of cyclin B1 and indirect inhibition of CDC2 kinase in several cancer cells. 23 In HBT-94 chondrosarcoma cells, BBR upregulated the expression of p53 and p21 by modulating activation of the PI3K/Akt and p38 signaling pathways, which resulted in G2/M phase arrest.…”

“…2 Recent studies showed that BBR reduced lipid levels and glycemic index, and exerted anti-tumor effects. [3][4][5][6][7] BBR lowered lipid levels via competitive inhibition of HMG-CoA reductase, and by interacting with the 3ʹ-UTR of the LDL receptor (LDLR) to improve the stability of LDLR mRNA. 8 In vivo experiment showed that BBR alleviated nonalcoholic fatty liver by activating SIRT3.…”