Abstract
Berberine, an isoquinoline alkaloid, is an active component of Ranunculaceae and Papaveraceae plant families. Berberine has been found to suppress growth of several tumor cell lines in vitro through the cell-type-dependent mechanism. Expression and activation of epidermal growth factor receptor (EGFR) is increased in colonic precancerous lesions and tumours, thus EGFR is considered a tumour promoter. The aim of this study was to investigate the effects and mechanisms of berberine on regulation of EGFR activity and proliferation in colonic tumor cell lines and in vivo. We reported that berberine significantly inhibited basal level and EGF-stimulated EGFR activation and proliferation in the immorto Min mouse colonic epithelial (IMCE) cells carrying the APC min mutation and human colonic carcinoma cell line, HT-29 cells. Berberine acted to inhibit proliferation through inducing G1/S and G2/M cell cycle arrest, which correlated with regulation of the checkpoint protein expression. In this study, we also showed that berberine stimulated ubiquitin ligase Cbl activation and Cbl's interaction with EGFR, and EGFR ubiquitinylation and down-regulation in these two cell lines in the presence or absence of EGF treatment. Knock-down Cbl expression blocked the effects of berberine on down-regulation of EGFR and inhibition of proliferation. Furthermore, berberine suppressed tumor growth in the HT-29 cell xenograft model. Cell proliferation and EGFR expression level was decreased by berberine treatment in this xenograft model and in colon epithelial cells of APC min/+ mice. Taken together, these data indicate that berberine enhances Cbl activity, resulting in down-regulation of EGFR expression and inhibition of proliferation in colon tumor cells.
Highlights
Berberine is an active component of Ranunculaceae and Papaveraceae families of plant
Berberine downregulates epidermal growth factor receptor (EGFR) expression and activates Cbl in colon tumor cells To determine the effects of berberine on regulation of EGFR activity in colon cancer cells, we chose two colonic tumor cell lines, the immorto Min mouse colonic epithelial (IMCE) cells carrying the APCmin mutation [20], and HT-29 cells which were isolated from human colonic carcinoma
In addition to regulation of basal levels of EGFR expression and activation, berberine was able to downregulate EGFR expression in IMCE and HT-29 cells treated with EGF (Figure 1B)
Summary
Berberine is an active component of Ranunculaceae and Papaveraceae families of plant. It represents one of well-studied naturally occurring isoquinoline alkaloids. Recent research focused on berberine’s anti-tumor effect has shown that berberine inhibits growth of broad tumor cell types derived from leukocytes, liver, lung, gastrointestinal tract, oral, skin, brain, bone, bladder, breast, cervix, and prostate [3]. Several mechanisms involved in berberine’s antitumor activity have been identified, which include stimulating caspase-dependent apoptosis and caspase-independent cell death by activation of apoptosisinducing factor, suppressing cancer cell growth and proliferation by induction of cell cycle arrest, and inhibiting metastasis by down-regulating matrix metalloproteinases [1]. Berberine-regulated signaling pathways involved in its anti-cancer effects have been found, which include p53, MAPK, and NF-kB [3,4]. The findings that mechanisms underlying berberine’s anti-cancer effects are different among tumor cell types indicate the cell type specific effect of berberine on inhibition of tumor development
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