Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer

Abstract

Background: As a natural alkaloid product isolated from Sophora alopecuroides. L, Sophoridine reshapes gastric cancer immune microenvironment via inhibiting chemotaxis and M2 polarization of tumor-associated macrophages (TAMs). However, the exact effects and underlying mechanism of Sophoridine on gastric cancer cells remains poorly known. Methods: The potential anti-tumor effects of Sophoridine on gastric cancer cell lines, including AGS and SGC7901 cells, were detected by CCK-8, EDU and colony forming assay, immunofluorescence, transwell assay, and flow cytometry. Molecular mechanisms of Sophoridine were investigated by siRNA transfection, nuclear/cytoplasmic extraction and western blot. The synergistic effects of Sophoridine with cisplatin on gastric cancer cells were further investigated in in vitro functional studies. Results: Sophoridine exhibited potent tumor-suppressive activities in gastric cancer cells, including inhibition of proliferation, colony formulation, migration and invasion, as well as induction of apoptosis. In addition, we further showed that Sophoridine induced G2/M cell cycle arrest via inhibiting double-stranded DNA breaks repair and enhanced the efficacy of cisplatin in gastric cancer cells. Molecular studies further revealed that Sophoridine promoted β-catenin degradation by enhancing Estrogen-related receptor gamma (ESRRG) expression, but not depended on ubiquitination-proteasome pathway, either TRIM33-mediated (GSK3β-independent) or altered GSK3β activity, and thus exerted potent tumor-suppressive activities. Conclusion: Sophoridine depends on targeting ESRRG/β-catenin pathway to exert tumor-suppressive activities in gastric cancer cells and enhances the anti-tumor effect of cisplatin. Our study provided the promising preclinical anti-tumor evidence for the potential application of Sophoridine against gastric cancer.

Genus Sophora: a comprehensive review on secondary chemical metabolites and their biological aspects from past achievements to future perspectives

“…Through activating p53 and Hippo signaling pathways, sophoridine ( 240 ) inhibited lung cancer cell growth and enhanced the cisplatin sensitivity (ur Rashid et al 2020 ; Zhou et al 2018d , 2020 ). The same compound 240 was reported to exert tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer (Peng et al 2020b ). Sophoridine ( 240 ) also reported to suppress macrophage-mediated immunosuppression through TLR4/IRF3 pathway, and subsequently upregulate CD8 + T cytotoxic function against gastric cancer (Zhuang et al 2020 ).…”

Update and New Insights on Future Cancer Drug Candidates From Plant-Based Alkaloids

“…Another study showed that sophoridine significantly inhibits survival, invasion, and migration of gastric cancer cells by enhancing estrogen-related receptor gamma expression, which leads to the degradation of β-catenin. Furthermore, it induces G2/M cell cycle arrest by inhibiting double-stranded DNA break repair and enhances the efficacy of cisplatin in gastric cancer cells ( Peng et al, 2020 ). Therefore, sophoridine may be a promising candidate for human gastric cancer treatment.…”

Research Progress in the Pharmacological Activities, Toxicities, and Pharmacokinetics of Sophoridine and Its Derivatives

“… [ 10 ] In vivo Nude mice 20, 40, and 80 μM Decreasing the PTEN protein expression, tumor volume and weight [ 10 ] In vitro HepG2 and Huh7 human HCC cell lines 20, 40, and 80 μM Reducing VEGFR2 expression and RAS/MEK/ERK axis [ 17 ] In vivo BALB/c nude mice 50 mg/kg, ip Inhibiting the tumour cell proliferation and angiogenesis. [ 17 ] In vitro BRL-3A cells 1, 2, and 3 mM Up-regulating intracellular ROS accumulation [ 16 ] In vitro MKN45 cells 8, 14 mM Down-regulation of HMGB3 protein expression [ 20 ] In vitro Gastric cancer cell lines (SGC7901 and AGS) 1, 3, and 5 μM Up-regulating ESRRG /β-catenin pathway [ 21 ] In vitro MFC cancer cells 2, 4, and 8 mM Up-regulating TLR4/IRF3 signal pathway and CD8+ T cytotoxic function against gastric cancer [ 12 ] In vitro SW480 cells 1.6, 3.2 mM Activating apoptosis-related proteins caspases (caspase −3, caspase-9 and caspase-7) and PARP regulation [ 13 ] In ...…”