title: Berberine induces senescence of human glioblastoma cells by downregulating the EGFR-MEK-ERK signaling pathway.
abstract: 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 IC50 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.
authors.affiliation: Key Laboratory of Experimental Teratology of Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Key Laboratory of Experimental Teratology of Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Xu
authors.affiliation: Key Laboratory of Experimental Teratology of Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Minnan
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Experimental Teratology of Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Key Laboratory of Experimental Teratology of Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Experimental Teratology of Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Xiyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Experimental Teratology of Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Zhaojian
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Experimental Teratology of Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Key Laboratory of Experimental Teratology of Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China. Department of Genetics/Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey. shaochangshun@sdu.edu.cn.
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001599:Berberine / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000378:metabolism
chemical_list: D001599:Berberine; D066246:ErbB Receptors; D048490:raf Kinases