Geraniin suppresses tumor cell growth and triggers apoptosis in human glioma via inhibition of STAT3 signaling

Abstract

Natural phytochemicals are attracting increasing interest as anticancer agents. The aim of this study is to evaluate the therapeutic potential of geraniin, a major ellagitannin extracted from Geranium sibiricum L., in human glioma. Human U87 and LN229 glioma cells were treated with different concentrations of geraniin, and cell viability, apoptosis, and gene expression were assessed. The involvement of STAT3 signaling in the action of geraniin was examined. We found that geraniin treatment for 48 h significantly (P \ 0.05) impaired the phosphorylation of STAT3 and reduced the expression of downstream target genes Bcl-xL, Mcl-1, Bcl-2, and cyclin D1. Exposure to geraniin led to a concentration-dependent decline in cell viability and increase in apoptosis in glioma cells, but had no significant impact on the viability of normal human astrocytes. Measurement of caspase-3 activity showed that geraniin-treated U87 and LN229 cells showed a 1.8-2.5-fold higher caspase-3 activity than control cells. Overexpression of constitutively active STAT3 significantly (P \ 0.05) reversed geraniin-mediated growth suppression and apoptosis, which was accompanied by restoration of Bcl-xL, Mcl-1, Bcl-2, and cyclin D1 expression. In an xenograft tumor mouse model, geraniin treatment significantly retarded tumor growth and induced apoptosis. Western blot analysis confirmed the suppression of STAT3 phosphorylation in glioma

microRNA cluster MC‐let‐7a‐1~let‐7d promotes autophagy and apoptosis of glioma cells by down‐regulating STAT3

“…Down-regulated STAT3 has been reported to effectively enhance autophagy as well as the apoptosis of GBM cells in orthotopic transplanted rat samples, while blockade of the STAT3 signaling pathway may also trigger the apoptosis of glioma cells. 18,19 The upstream regulatory miRNAs of STAT3 were explored by the bioinformatics websites. The top 50 miRNAs targeting STAT3 were selected.…”

Prospect of natural products in glioma: A novel avenue in glioma management

“…It works through AKT inactivation and p38MAPK and JNK activation (Wang, Fu, et al, ). Shikonin is another anticancer agent from the natural source (Ren et al, ). It increases oxidative stress by promoting ROS generation from mitochondria in neuroblastoma.…”

Geraniin Differentially Modulates Chromosome Stability of Colon Cancer and Noncancerous Cells by Oppositely Regulating their Spindle Assembly Checkpoint

“…Geraniin has been found to inhibit proliferation and induce apoptosis in multiple human tumor cells [Lee et al ; Li et al ; Ko ; Zhai et al ; Ren et al ; Wang et al ; Wang et al ]. However, molecular mechanism underlying the antitumor effects of geraniin has not been fully evaluated.…”

“…This means SAC is a more favorable therapeutic target because it is more critical for the survival of a cancer cell than a normal cell. Geraniin has been found to inhibit proliferation and induce apoptosis in multiple human tumor cells [Lee et al 2008;Li et al 2013;Ko 2015;Zhai et al 2016;Ren et al 2017;Wang et al 2017a;Wang et al 2017b]. However, molecular mechanism underlying the antitumor effects of geraniin has not been fully evaluated.…”

“…The natural occurrence of geraniin has been verified in other ethnopharmacological important plants, such as a broad species of genus Geranium (e.g., G. sibiricum and G. thunbergii ), highlighting its role as an active ingredient in traditional medicines [Cheng et al ]. Recently, a large number of in vitro and in vivo experiments have reported that geraniin induces apoptosis in human glioma [Ren et al ], breast cancer [Zhai et al ], ovarian cancer [Wang et al ], lung cancer [Li et al ; Ko ], melanoma [Lee et al ], and osteosarcoma cells [Wang et al ], whereas leaving untransformed cells unaffected. This selectivity makes geraniin ideal for cancer treatment.…”