Abstract：
Despite significant advances in the treatment of colorectal cancer (CRC), identification of novel targets and treatment options are imperative for improving its prognosis and survival rates. The mitochondrial SIRT3 and SHMT2 have key roles in metabolic reprogramming and cell proliferation. This study investigated the potential use of the natural product apigenin in CRC treatment employing both in vivo and in vitro models and explored the role of SIRT3 and SHMT2 in apigenin-induced CRC apoptosis. The role of SHMT2 in CRC patients\' survival was verified using TCGA database. In vivo, apigenin treatment restored the normal colon appearance. On the molecular level, apigenin augmented the immunohistochemical expression of cleaved caspase-3 and attenuated SIRT3 and SHMT2 mRNA expression CRC patients with decreased SHMT2 expression had improved overall and disease-free survival rates. In vitro, apigenin reduced the cell viability in a time-dependent manner, induced G0/G1 cell cycle arrest, and increased the apoptotic cell population compared to the untreated control. Mechanistically, apigenin treatment mitigated the expression of SHMT2, SIRT3, and its upstream long intergenic noncoding RNA LINC01234 in CRC cells. Conclusively, apigenin induces caspase-3-dependent apoptosis in CRC through modulation of SIRT3-triggered mitochondrial pathway suggesting it as a promising therapeutic agent to improve patient outcomes.
摘要：
尽管在结直肠癌（CRC）的治疗方面取得了重大进展，确定新的靶点和治疗方案对于改善其预后和生存率至关重要.线粒体SIRT3和SHMT2在代谢重编程和细胞增殖中具有关键作用。这项研究调查了天然产物芹菜素在使用体内和体外模型进行CRC治疗中的潜在用途，并探讨了SIRT3和SHMT2在芹菜素诱导的CRC凋亡中的作用。SHMT2在CRC患者生存中的作用已使用TCGA数据库进行验证。在体内,芹菜素治疗恢复正常的结肠外观。在分子水平上,芹菜素以剂量依赖的方式增强了裂解的caspase-3的免疫组织化学表达，并减弱了SIRT3和SHMT2mRNA的表达。SHMT2表达降低的CRC患者总体生存率和无病生存率均有所提高。体外，芹菜素以时间依赖的方式降低细胞活力，诱导G0/G1细胞周期阻滞，并且与未处理的对照相比增加了凋亡细胞群体。机械上,芹菜素处理降低了SHMT2,SIRT3及其上游LINC01234在CRC细胞中的表达.最后，芹菜素通过调节SIRT3触发的线粒体途径诱导CRC中caspase-3依赖性细胞凋亡,提示其是改善患者预后的有前景的治疗剂.
