Degradation of MDM2 by the Interaction between Berberine and DAXX Leads to Potent Apoptosis in MDM2-Overexpressing Cancer Cells

Zhang, Xiaoling; Gu, Liqun; Li, Jiansha; Shah, Noopur; He, Jing; Yang, Lin; Hu, Qun; Zhou, Mi

doi:10.1158/0008-5472.can-10-1546

Cited by 114 publications

(116 citation statements)

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“…Consistent with its long-standing liver protective effects, berberine has been shown to exhibit anticachectic effect in a colon cancer-bearing mouse model (25), and to induce the growth related gene rcl, in a rat hepatoma cell line (27). Recent reports indicate that p53 and p38 MAPK pathways are involved in berberine anticancer activity (28,29). Although these studies have provided some understanding about the functions of berberine, the exact molecular mechanisms are unknown.…”

Section: Discussionmentioning

confidence: 91%

Berberine inhibits the proliferation of colon cancer cells by inactivating Wnt/β-catenin signaling

2012

Int J Oncol

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Abstract. Colon cancer is one of the most common malignancies, mainly initiated by the abnormal activation of Wnt/β-catenin signaling. In this study, we investigated the proliferation inhibitory effect of berberine on colon cancer cells and the molecular basis underlying this effect. With the viability, apoptosis and cell cycle assay, we demonstrated that berberine can inhibit proliferation, induce apoptosis and cell cycle arrest in colon cancer cells. In in vivo investigation, we demonstrated that berberine can prevent the colon cancer formation initiated by dimethylhydrazine (DMH) and dextran sodium sulfate (DSS) in rats. We employed Western blotting, reverse transcription and polymerase chain reaction, special antagonist, overexpression and knockdown techniques to dissect the possible molecular mechanisms mediating the function of berberine. We found that the protein levels of β-catenin in the nucleus and cytoplasm were all reduced after treating the colon cancer cells with berberine, and this may not result from accelerating the degradation of β-catenin in the cytoplasm, but from inhibiting the mRNA expression of β-catenin. Our results indicate that berberine can be a potential chemoprevention and chemotherapy agent for human colon cancer by targeting Wnt/β-catenin signaling. IntroductionColon cancer, which causes considerable morbidity and mortality, is one of the most common malignancies and primarily initiated by the abnormal activation of Wnt/β-catenin signaling pathway (1). Although the treatment options have substantially increased and substantial benefits have been achieved for some patients, overall progress has been more modest than had been hoped (2). Thus, there is a great clinical need to explore new agents for the treatment of colon cancer. Herbal and natural products are valuable resources for anticancer drugs (3,4). Plant derived active components, their semi-synthetic and synthetic analogs have served as one of the major sources for anticancer drugs (5-8). Some plant derived compounds have been used for anticancer drugs for a few years (6), including vinblastine, vincristine, etoposide, teniposide, taxol, and camptothecin. Thus, natural products acted as a major role in cancer chemotherapy for the past decades (6).It has been reported that Chinese herb Coptis chinensis was a promising anticancer agent, of which the most active ingredient is berberine. In fact, berberine, an isoquinoline alkaline, has been used as anti-microbial, anti-diarrheal and anti-inflammatory agent for thousands of years (9). Because of its low toxicity and low cost, there has recently been considerable interest in the possible use of berberine in the treatment of human cancers. Several studies suggest that berberine can inhibit cell proliferation, also it has been reported that berberine can inhibit carcinogen, such as DMH, induced formation of aberrant crypt foci (ACF) in the rat colon, which is usually considered to be preneoplastic lesions of colon mucosa. However, the exact mechanism is not fully understood yet.We ...

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Section: Discussionmentioning

confidence: 91%

Berberine inhibits the proliferation of colon cancer cells by inactivating Wnt/β-catenin signaling

2012

Int J Oncol

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“…Berberine can induce apoptosis in a variety of cancer cells (12,13,(18)(19)(20). We, therefore, determined whether berberine could also induce apoptosis of glioblastoma cells.…”

Section: Berberine Induces Cellular Senescence Of Glioblastoma Cellsmentioning

confidence: 99%

Berberine Induces Senescence of Human Glioblastoma Cells by Downregulating the EGFR–MEK–ERK Signaling Pathway

Zhao

et al. 2015

Molecular Cancer Therapeutics

108

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Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and has a poor prognosis. We, here, report a potent antitumor effect of berberine, an isoquinoline alkaloid, on GBM. Berberine was found to have an IC 50 that is much lower than temozolomide in vitro in U87, U251, and U118 glioblastoma cells. Although previous studies showed that berberine primarily exerts its anticancer effect by inducing cell-cycle arrest, apoptosis, and autophagy, we observed that the antitumor effect of berberine on glioblastoma cells was primarily achieved through induction of cellular senescence. In glioblastoma cells treated with berberine, the level of epidermal growth factor receptor (EGFR) was greatly reduced. Examination of the activities of the kinases downstream of EGFR revealed that the RAF-MEK-ERK signaling pathway was remarkably inhibited, whereas AKT phosphorylation was not altered. Pharmacologic inhibition or RNA interference of EGFR similarly induced cellular senescence of glioblastoma cells. Furthermore, the cellular senescence induced by berberine could be rescued by introduction of a constitutive active MKK. Berberine also potently inhibited the growth of tumor xenografts, which was accompanied by downregulation of EGFR and induction of senescence. Our findings thus revealed a new route by which berberine exerts its anticancer activity. Because EGFR is commonly upregulated in glioblastoma, the demonstration of effective inhibition of EGFR by berberine points to the possibility of using berberine in the treatment of patients with glioblastoma.

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“…Zhang et al also reported that berberine triggers apoptosis in acute lymphoblastic leukemia cells through down-regulating the MDM2 (21). Because the role of p53 has been emerging in cell cycle and apoptosis of cancer cells, we also investigated the effect of berberine on p53 mRNA and protein expression in human breast cancer cells.…”

Section: Discussionmentioning

confidence: 90%

“…The function of p53 is known in a variety of cell types including the arrest of cell cycle, cellular senescence, and apoptosis (19,21). p21 and Polo-like kinase 1 are important targets of p53 for G1/S and G2-M cell cycle checkpoint activation, respectively (15).…”

Section: Discussionmentioning

confidence: 99%

Effect of berberine on p53 expression by TPA in breast cancer cells

Kim

Han²,

Kim³

et al. 2011

Oncol Rep

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Abstract. Berberine (BBR), an isoquinoline derivative alkaloid compound, has been reported to have anti-oxidant and anti-carcinogenic effects. A loss of functional p53 is involved with an increased risk of cancer proliferation and metastasis. Here, we investigated the effect of BBR on the transcriptional activity and the protein expression of p53 in p53-positive (wildtype, MCF7 cells) and p53-negative (mutant, MDA-MB231 cells) human breast cancer cells. Our results showed that the basal level of p53 mRNA and protein expression was increased by BBR treatment. However, tumor promoter, TPA, decreased the level of p53 mRNA and protein expression in MCF7 cells with wild-type p53. In addition, TPA-induced down-regulation of p53 mRNA and protein expression was increased by UO126, but not by SP600125 and SB203580. To verify the regulatory mechanism of p53 protein expression, we investigated the effects of proteasomal inhibitors (ALLN and MG132) or a lysosomal inhibitor (chloroquine) on TPA-induced down-regulation of p53. We observed that TPA-induced downregulation of p53 protein was prevented by ALLN and MG132, but not by chloroquine. Further, we investigated the effect of BBR on TPA-induced down-regulation of p53 mRNA and protein levels. Interestingly, the levels of TPA-induced downregulation of p53 mRNA and protein were prevented by BBR, but MDA-MB231 cells with mutated p53 were not affected. In addition, TPA-induced down-regulation of p53 mRNA was also prevented by BBR. Taken together, we suggest that BBR may be used as an effective ingredient for anticancer products, which trigger the transcriptional activity and the inhibition of the degradation of p53, a tumor suppressor gene, in human breast cancer.

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Degradation of MDM2 by the Interaction between Berberine and DAXX Leads to Potent Apoptosis in MDM2-Overexpressing Cancer Cells

Cited by 114 publications

References 37 publications

Berberine inhibits the proliferation of colon cancer cells by inactivating Wnt/β-catenin signaling

Berberine inhibits the proliferation of colon cancer cells by inactivating Wnt/β-catenin signaling

Berberine Induces Senescence of Human Glioblastoma Cells by Downregulating the EGFR–MEK–ERK Signaling Pathway

Effect of berberine on p53 expression by TPA in breast cancer cells

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