Matrine induces senescence of human glioblastoma cells through suppression of the IGF1/PI3K/AKT/p27 signaling pathway

Abstract

BackgroundMatrine, a traditional Chinese medicine, has recently been shown to have antitumor properties in diverse cancer cells. Here, we explored the effect of matrine on human glioblastoma multiforme (GBM) cells.MethodsGlioblastoma multiforme cell lines were treated with matrine to assess proliferation and viability using EdU and CCK8 assays. SA‐β‐gal assays were used to evaluate cellular senescence, and a cytokine array and ELISA assay were used to screen for secreted cytokines altered in GBM cells after matrine treatment. Immunohistochemistry and Western blot analysis were performed to evaluate protein levels in matrine‐treated cell lines and in samples obtained from orthotopic xenografts. Specific activators of AKT and IGF1 were used to identify the pathways mediating the effect.ResultsMatrine potently inhibited growth of GBM cell lines in vitro. Based on in situ assays, growth arrest induced by matrine was primarily achieved through induction of cellular senescence. Matrine treatment led to decreased expression of proteins involved in promoting cell growth, IGF1, PI3K, and pAKT. Exposure of cells to a small molecule activating AKT (SC79) and recombinant IGF1 led to a reduced number of senescent SA‐β‐gal‐positive cells in the presence of matrine. Finally, matrine inhibited growth of orthotopic xenografts established from luciferase‐stable‐U251 or luciferase‐stable‐P3 cells and prolonged overall survival in mice.ConclusionsThese results indicated that matrine arrested cell growth through inhibition of IGF1/PI3K/AKT signaling. Matrine warrants further investigation as a potential therapy in the treatment of patients with GBM.

Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

“…In addition, TMZ combined with amlexanox e caciously reduced the tumor volume and improved the survival of mice in the xenograft model in vivo. To date, a growing number of studies have focused on the inhibition of the AKT signaling pathway with combined administration in GBM and other tumors [7,[29][30][31][32][33][34]. Zhiyun Yu and his colleagues suggested that TMZ combined with NVP-BEZ235 synergistically inhibited GBM cell proliferation though downregulating AKT/mTOR signaling pathway [4], which was similar to our ndings.…”

Epigallocatechin‐3‐gallate induces telomere shortening and clastogenic damage in glioblastoma cells

“…Nonetheless, U251 cells have a mutated p53 (Zhang et al, 1996), and the p53/p21 axis is probably hampered or disrupted (Costanzi-Strauss et al, 1998;Abe et al, 2001). These findings, together with past published works (Sufit et al, 2016;Zhou et al, 2018) raise the question of which pathways (e.g., CHK2) are involved in the onset of senescence in p53-defective glioblastoma cells. In agreement with these studies, after treatment with EGCG, even at the highest dose, we found no induction of p21, neither by Western blot (data not shown), nor by immunofluorescence (Fig.…”

“…4 and 6). Indeed, Lee et al (2011) observed increased p21 expression in U251 cells only after irradiation with very high doses (>20 Gy) and Sufit et al (2016) and Zhou et al (2018) detected induction of senescence (revealed by β-galactosidase assay) in MERTk-inhibited and matrine-treated (respectively) U251 cells without induction of p21. This is not surprising, as p21 not only plays a role in senescence, but is also essential in many aspects of the cell cycle, and, in fact, is rarely mutated in cancer cells (Dijkstra et al, 2010).…”

D-galactose induces senescence of glioblastoma cells through YAP-CDK6 pathway

“…Various drugs, apart from, D-gal-induced GBM cell senescence model, have been found to induce in vitro senescence of GBM cells. These include berberine [ 37 ], flavokawain B (FKB), a natural kava chalcone [ 38 ], and matrine [ 39 ]. However, different cell senescence models show different disadvantages.…”

“…The mechanisms underlying the senescence of GBM cells may vary under different conditions [ 37 , 39 , 42 ]. For example, berberine induces senescence of GBM cells by downregulating the EGFR-MEK-ERK signaling pathway [ 37 ].…”