Berberine inhibits Rho GTPases and cell migration at low doses but induces G2 arrest and apoptosis at high doses in human cancer cells.

Berberine is an active ingredient extracted from Coptidis rhizoma which has been used for centuries as a traditional Chinese medicine for treatment of inflammatory diseases. Recent studies have indicated that berberine has anticancer properties. Berberine arrested cell growth and inhibited cell migration in various cancer cell lines. In this study, we examined the effects of berberine on HONE1 cells, which have been commonly used as a cell model for nasopharyngeal carcinoma. We observed the inhibitory effects of berberine on HONE1 cells at a high dosage (>150 microM). Berberine effectively induced the mitotic arrest of HONE1 cells at 300 microM which was associated with apoptosis. Berberine had differential intracellular localization at low and high doses. At a low dose (50 microM), berberine was localized in the mitochondria while at a high dose (300 microM), berberine was localized in the nucleus which may have induced mitotic arrest. Berberine effectively inhibited cell migration and invasion at low doses. Using a specific GST pull-down assay of activated Rho GTPases, we demonstrated that berberine suppressed the activation of Rho GTPases including RhoA, Cdc42 and Rac1. This indicates a novel function of berberine in the suppression of Rho GTPase signaling to mediate its inhibitory action on cell migration and motility. The potential of berberine to inhibit cancer metastasis in cancer warrants further investigation.

[1]  S. Katiyar,et al.  p53 cooperates berberine‐induced growth inhibition and apoptosis of non‐small cell human lung cancer cells in vitro and tumor xenograft growth in vivo , 2009, Molecular carcinogenesis.

[2]  B. Aggarwal,et al.  Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis. , 2008, Cancer research.

[3]  A. Ridley,et al.  Rho GTPases in cancer cell biology , 2008, FEBS letters.

[4]  Yi Feng,et al.  [Explore new clinical application of Huanglian and corresponding compound prescriptions from their traditional use]. , 2008, Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica.

[5]  P. Oliveira,et al.  Different concentrations of berberine result in distinct cellular localization patterns and cell cycle effects in a melanoma cell line , 2008, Cancer Chemotherapy and Pharmacology.

[6]  Seung Joon Baek,et al.  Berberine, a natural isoquinoline alkaloid, induces NAG-1 and ATF3 expression in human colorectal cancer cells. , 2007, Cancer letters.

[7]  John G. Collard,et al.  Rho GTPases: functions and association with cancer , 2007, Clinical & Experimental Metastasis.

[8]  Jai-Sing Yang,et al.  Berberine induces apoptosis in human HSC-3 oral cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway. , 2007, Anticancer research.

[9]  L. Cipak,et al.  Berberine induces apoptosis through a mitochondrial/caspase pathway in human promonocytic U937 cells. , 2007, Toxicology in vitro : an international journal published in association with BIBRA.

[10]  Shun-Fa Yang,et al.  Berberine induces apoptosis in SW620 human colonic carcinoma cells through generation of reactive oxygen species and activation of JNK/p38 MAPK and FasL , 2007, Archives of Toxicology.

[11]  S. Katiyar,et al.  Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki-Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARP. , 2006, Carcinogenesis.

[12]  Y. Hsieh,et al.  Inhibitory effect of berberine on the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2. , 2006, Toxicology and applied pharmacology.

[13]  M. Tatsuta,et al.  Inactivation of Rho GTPases by p190 RhoGAP reduces human pancreatic cancer cell invasion and metastasis , 2006, Cancer science.

[14]  Jing-Gung Chung,et al.  Down-regulation of cyclin B1 and up-regulation of Wee1 by berberine promotes entry of leukemia cells into the G2/M-phase of the cell cycle. , 2006, Anticancer research.

[15]  S. Katiyar,et al.  Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells , 2006, Molecular Cancer Therapeutics.

[16]  Jai-Sing Yang,et al.  Berberine induces cell cycle arrest and apoptosis in human gastric carcinoma SNU-5 cell line. , 2006, World journal of gastroenterology.

[17]  Chengwei He,et al.  The extract of huanglian, a medicinal herb, induces cell growth arrest and apoptosis by upregulation of interferon-β and TNF-α in human breast cancer cells , 2005 .

[18]  N. Iizuka,et al.  Molecular dissection of a medicinal herb with anti-tumor activity by oligonucleotide microarray. , 2005, Life sciences.

[19]  Frederick P. Li,et al.  The extract of huanglian, a medicinal herb, induces cell growth arrest and apoptosis by upregulation of interferon-beta and TNF-alpha in human breast cancer cells. , 2005, Carcinogenesis.

[20]  Chun-chung Lee,et al.  Berberine Inhibits HIF-1α Expression via Enhanced Proteolysis , 2004 .

[21]  H. Kung,et al.  Suppression of Epstein-Barr virus-encoded latent membrane protein-1 by RNA interference inhibits the metastatic potential of nasopharyngeal carcinoma cells. , 2004, Biochemical and biophysical research communications.

[22]  Chun-chung Lee,et al.  Berberine inhibits HIF-1alpha expression via enhanced proteolysis. , 2004, Molecular pharmacology.

[23]  N. Iizuka,et al.  Identification of common or distinct genes related to antitumor activities of a medicinal herb and its major component by oligonucleotide microarray , 2003, International journal of cancer.

[24]  H. Kung,et al.  Identification of an Autoinhibitory Domain of p21-activated Protein Kinase 5* , 2003, Journal of Biological Chemistry.

[25]  L. Cipak,et al.  Effect of berberine on proliferation, cell cycle and apoptosis in HeLa and L1210 cells , 2003, The Journal of pharmacy and pharmacology.

[26]  Chih-Hung Hsu,et al.  Prognostic Value of Multidrug Resistance 1, Glutathione-S-Transferase-π and p53 in Advanced Nasopharyngeal Carcinoma Treated with Systemic Chemotherapy , 2002, Oncology.

[27]  A. Ridley.  Rho GTPases and cell migration. , 2001, Journal of cell science.

[28]  G. Schwartz,et al.  Huanglian, A chinese herbal extract, inhibits cell growth by suppressing the expression of cyclin B1 and inhibiting CDC2 kinase activity in human cancer cells. , 2000, Molecular pharmacology.

[29]  Tian Daofa.  A Clinical Observation on the Inhibitory Effect of Yiqijiedu Granules to the Infection Activity of EBV in Population Highly Susceptible to NPC , 2000 .

[30]  N. Iizuka,et al.  Inhibitory effect of Coptidis Rhizoma and berberine on the proliferation of human esophageal cancer cell lines. , 2000, Cancer letters.

[31]  C. Tsai,et al.  Establishment and characterization of two epithelial tumor cell lines (hne‐1 and hone‐1) latently infected with epstein‐barr virus and derived from nasopharyngeal carcinomas , 1990, International journal of cancer.

[32]  Pelayo Vilar,et al.  Nasopharyngeal Carcinoma , 1966 .