title: Berberine hydrochloride IL-8 dependently inhibits invasion and IL-8-independently promotes cell apoptosis in MDA-MB-231 cells.
abstract: Breast cancer, the leading cause of cancer-related mortality worldwide in females, has high metastastic and recurrence rates. The aim of the present study was to evaluate the anti-metastatic and anticancer in situ effect of berberine hydrochloride (BER) in MDA-MB-231 cells. BER dose-dependently inhibited proliferation and the IL-8 secretion of MDA-MB-231 cells. Additional experiments revealed that the inactivation of PI3K, JAK2, NF-κB and AP-1 by BER contributed to the decreased IL-8 secretion. BER abrogated cell invasion induced by IL-8 accompanied with the downregulation of the gene expression of MMP-2, EGF, E-cadherin, bFGF and fibronectin. In addition, BER reduced cell motility but induced G2/M arrest and cell apoptosis in an IL-8‑independent manner. BER modulated multiple signaling pathway molecules involved in the regulation of cell apoptosis, including activation of p38 MAPK and JNK and deactivation of JAK2, p85 PI3K, Akt and NF-κB. The enhanced cell apoptosis induced by BER was eliminated by inhibitors of p38 MAPK and JNK but was strengthened by activator of p38 MAPK. Thus, BER inhibited cell metastasis partly through the IL-8 mediated pathway while it induced G2/M arrest and promoted cell apoptosis through the IL-8 independent pathway. Apoptosis induced by BER was mediated by crosstalks of various pathways including activation of p38 MAPK and JNK pathways and inactivation of Jak2/PI3K/NF-κB/AP-1 pathways. The results suggested that BER may be an efficient and safe drug candidate for treating highly metastatic breast cancer.
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai 201203, P.R. China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai 201203, P.R. China.
authors.forename: Shu-Juan
authors.initials: SJ
authors.lastname: Zhao
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai 201203, P.R. China.
authors.forename: Hai-Lian
authors.initials: HL
authors.lastname: Shi
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai 201203, P.R. China.
authors.forename: Shui-Ping
authors.initials: SP
authors.lastname: Qiu
authors.affiliation: Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, XuHui, Shanghai 200032, P.R. China.
authors.forename: Jian-Qun
authors.initials: JQ
authors.lastname: Xie
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai 201203, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai 201203, P.R. China.
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai 201203, P.R. China.
authors.forename: Zheng-Tao
authors.initials: ZT
authors.lastname: Wang
authors.affiliation: Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, XuHui, Shanghai 200032, P.R. China.
authors.forename: Jian-Ye
authors.initials: JY
authors.lastname: Yuan
authors.affiliation: Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai 201203, P.R. China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Wu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001599:Berberine / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: D016209:Interleukin-8; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D001599:Berberine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases