Songorine suppresses cell growth and metastasis in epithelial ovarian cancer via the Bcl‑2/Bax and GSK3β/β‑catenin signaling pathways

Abstract

Epithelial ovarian cancer (EOC) is the most frequent cause of cancer-associated mortality among all types of gynecological cancer. The high recurrence rate and the poor 5-year survival rate indicate that more effective therapeutic strategies are required. The aim of the present study was to investigate the role and potential mechanisms of songorine in treating EOC. EOC cells were cultured with different concentrations of songorine, following which MTT and flow cytometric analyses were conducted to measure cell viability and apoptosis. Wound healing and Transwell assays were used to detect cell migration and invasion abilities. Furthermore, associated molecules in the glycogen synthase kinase (GSK)-3β/β-catenin and B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X (Bax) signaling pathways were semi-quantified by western blotting. Finally, tumor size measurements, pathological observations, western blot analysis and toxicological evaluations were performed in SKOV-3 tumor-bearing BALB/c nude mice to investigate the efficacy and safety of songorine. As expected, songorine inhibited EOC cell survival, invasion and migration, promoted EOC cell apoptosis and suppressed mammalian EOC tumorigenic behavior. In particular, GSK3β inhibitor treatment restored the songorine-induced regulation of the GSK3β/ β-catenin signaling pathway. Furthermore, in the in vitro and in vivo experiments, songorine consistently downregulated the expression of N-cadherin, vimentin, matrix metalloproteinase (MMP)-2, MMP-9, phosphorylated-GSK3β, β-catenin and Bcl-2, and upregulated the expression of E-cadherin, cleaved caspase-3, cleaved caspase-9 and Bax. In conclusion, songorine exerted its anticancer effect through the GSK3β/β-catenin and Bcl-2/Bax signaling pathways. These results highlight the potential use of songorine as a novel therapeutic agent for EOC.

Molecular mechanisms of action and chemosensitization of tumor cells in ovarian cancer by phytochemicals: A narrative review on pre‐clinical and clinical studies

“…Songorine (30) exerted its antitumor activity via the glycogen synthase kinase‐3 beta (GSK3/β‐catenin) and Bcl‐2/Bax signaling pathways. These findings highlight the potential use of songorine as a novel therapeutic agent for ovarian cancer, as the increased stability of GSK3 protein can hasten the degradation of β‐catenin, resulting in negative regulation of MMP secretion and inhibiting tumor invasion and migration (Zhang, Dong, et al, 2019).…”

Inhibition of MEG3 ameliorates cardiomyocyte apoptosis and autophagy by regulating the expression of miRNA-129-5p in a mouse model of heart failure

“…PI3 K/Akt is a pathway related to growth and proliferation, and activated Akt can activate or inhibit its downstream target protein GSK-3β through phosphorylation to play a regulatory role. GSK-3β is recognized as one of the substrates of PI3 K/Akt in the body, which can adjust the ratio of Bax, and then regulate cell cycle and apoptosis [ 36 ]. Recent data indicated that miR-1298 mimic reduced apoptosis in ischemia-reperfusion injured cardiomyocytes by increasing the protein expression of Bcl-2 and p-GSK3β and decreasing the protein expression of Bax [ 37 ].…”

Development of an ultra‐high‐performance liquid chromatography–tandem mass spectrometry method for the simultaneous determination of crassicauline A, fuziline, karacoline, and songorine in rat plasma and application in their pharmacokinetics

“…Karacoline, an amine‐type alkaloid found in the plant Aconitum kusnezoffii , reduces degradation of the extracellular matrix in intervertebral disc degeneration via the nuclear factor‐kappa B (NF‐κB) signaling pathway (Zhou et al, 2020). Songorine is an amine‐type alkaloid isolated from the genus Aconitum and has anticancer, antiarrhythmic, and anti‐inflammatory activities (Zhang et al, 2019).…”