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. 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. 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. 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.

中文翻译：

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槐定啶通过促进ESRRG介导的胃癌中β-catenin降解而发挥抑瘤活性。

作为从苦参中分离出的天然生物碱产品。L，槐定啶通过抑制肿瘤相关巨噬细胞（TAMs）的趋化性和M2极化来重塑胃癌免疫微环境。然而，槐定碱对胃癌细胞的确切作用和潜在机制仍知之甚少。通过CCK-8，EDU和集落形成测定，免疫荧光，transwell测定和流式细胞术检测了槐定定对胃癌细胞系（包括AGS和SGC7901细胞）的潜在抗肿瘤作用。通过siRNA转染，核/细胞质提取和western blot研究了槐定碱的分子机制。在体外功能研究中进一步研究了槐定碱与顺铂对胃癌细胞的协同作用。槐定碱在胃癌细胞中表现出有效的肿瘤抑制活性，包括抑制增殖，集落形成，迁移和侵袭以及诱导凋亡。此外，我们进一步表明槐定碱通过抑制双链DNA断裂修复来诱导G2 / M细胞周期停滞，并增强了顺铂在胃癌细胞中的功效。分子研究进一步表明，槐定碱通过增强雌激素相关受体γ（ESRRG）的表达来促进β-catenin降解，但不依赖于泛素化蛋白酶体途径，无论是TRIM33介导的（独立于GSK3β的）还是改变了GSK3β的活性，因此均发挥了作用肿瘤抑制活性。槐定碱依赖于靶向ESRRG /β-catenin途径在胃癌细胞中发挥肿瘤抑制活性，并增强顺铂的抗肿瘤作用。我们的研究为槐定定抗胃癌的潜在应用提供了有希望的临床前抗肿瘤证据。