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.
Highlights
Overexpression of Cyclin D1 in various human cancers is regarded as a key mechanism underlying tumor angiogenesis, progression, and metastasis [1,2,3,4,5,6]
Our findings reveal that berberine could rapidly inhibit Cyclin D1 expression in time- and dose-dependent manner but is independent on cell cycle
We observed that berberine exhibits dose- and time-dependent inhibition on Cyclin D1 expression in human hepatoma cells
Summary
Overexpression of Cyclin D1 in various human cancers is regarded as a key mechanism underlying tumor angiogenesis, progression, and metastasis [1,2,3,4,5,6]. Cyclin D1 overexpression is found to enhance cancer cells resistance to chemotherapeutic agents [7]. Disruption of Cyclin D1 proteolysis is one of the major mechanisms that cancer cells accumulate Cyclin D1 [8]. Several studies revealed that inhibitory effect of berberine on Cyclin D1 expression in various cancer cell lines including neuroblastoma SK-N-SH & SK-N-MC cells [14], human epidermoid carcinoma A431 cells [15], human prostate carcinoma LNCap, DU145 & PC-3 cells [16], human leukemia cells HL-60 [17], and pulmonary giant cell carcinoma
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