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 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.

Pan-HER Inhibitor Augments Radiation Response in Human Lung and Head and Neck Cancer Models

“…5B). These results corroborate other reports where EGFR inhibitors induce an antitumor impact through cellular senescence (26) and suggest an additional mechanism by which Pan-HER may increase radiosensitization of NSCLC and HNSCC cells.…”

Berberine Induces Cell Cycle Arrest in Cholangiocarcinoma Cell Lines <i>via</i> Inhibition of NF-κB and STAT3 Pathways

“…35) Suppression of the EGFR signaling pathway by berberine has been reported by several groups. 31,36,37) Berberine inhibited growth and promoted apoptosis of breast cancer cells 38) and the mechanism was shown to be via inhibition of the HER2 signaling pathway. This evidence suggests the inhibition of ERK upstream stimuli, EGFR and HER2 being the mechanism by which berberine affected the ERK pathway as observed in the current study.…”

Berberine inhibits enterovirus 71 replication by downregulating the MEK/ERK signaling pathway and autophagy

“…1a), an isoquinoline alkaloid isolated from Berberis vulgaris L. , has been reported to have multi pharmacological effects such as antidiarrheal effect [18], antibacterial effect [19], hypotensive effect [20], and antiviral activity [21, 22]. Most of these pharmacological effects is known to be associated with the mechanisms that BBR regulates signaling pathway in vitro, such as, EGFR/MEK/ERK signaling pathway [23], NF-κB pathway [22], AMPK/mTOR signaling pathway [24]. In addition, Deng et al demonstrated that BBR attenuates autophagy in adipocytes by targeting BECN1 [25].…”