Abstract：
Flavonoids, including fisetin, have been linked to a reduced risk of colorectal cancer (CRC) and have potential therapeutic applications for the condition. Fisetin, a natural flavonoid found in various fruits and vegetables, has shown promise in managing CRC due to its diverse biological activities. It has been found to influence key cell signaling pathways related to inflammation, angiogenesis, apoptosis, and transcription factors. The results of this study demonstrate that fisetin induces colon cancer cell apoptosis through multiple mechanisms. It impacts the p53 pathway, leading to increased levels of p53 and decreased levels of murine double minute 2, contributing to apoptosis induction. Fisetin also triggers the release of important components in the apoptotic process, such as second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI and cytochrome c. Furthermore, fisetin inhibits the cyclooxygenase-2 and wingless-related integration site (Wnt)/epidermal growth factor receptor/nuclear factor kappa B signaling pathways, reducing Wnt target gene expression and hindering colony formation. It achieves this by regulating the activities of cyclin-dependent kinase 2 and cyclin-dependent kinase 4, reducing retinoblastoma protein phosphorylation, decreasing cyclin E levels, and increasing p21 levels, ultimately influencing E2 promoter binding factor 1 and cell division cycle 2 (CDC2) protein levels. Additionally, fisetin exhibits various effects on CRC cells, including inhibiting the phosphorylation of Y-box binding protein 1 and ribosomal S6 kinase, promoting the phosphorylation of extracellular signal-regulated kinase 1/2, and disrupting the repair process of DNA double-strand breaks. Moreover, fisetin serves as an adjunct therapy for the prevention and treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA)-mutant CRC, resulting in a reduction in phosphatidylinositol-3 kinase (PI3K) expression, Ak strain transforming phosphorylation, mTOR activity, and downstream target proteins in CRC cells with a PIK3CA mutation. These findings highlight the multifaceted potential of fisetin in managing CRC and position it as a promising candidate for future therapy development.
摘要：
黄酮类化合物,包括Fisetin,与降低结直肠癌（CRC）的风险有关，并具有潜在的治疗应用。Fisetin,一种在各种水果和蔬菜中发现的天然类黄酮，由于其多样化的生物活性，在管理CRC方面显示出了希望。已经发现它影响与炎症相关的关键细胞信号通路，血管生成,凋亡，和转录因子。这项研究的结果表明，非塞素通过多种机制诱导结肠癌细胞凋亡。它影响p53通路，导致p53水平升高和鼠类双分钟2水平降低，有助于细胞凋亡诱导。Fisetin还触发凋亡过程中重要成分的释放，如第二线粒体来源的caspase激活剂/凋亡结合蛋白的直接抑制剂，具有低pI和细胞色素c。此外，非塞素抑制环氧合酶-2和无翼相关整合位点（Wnt）/表皮生长因子受体/核因子κB信号通路，降低Wnt靶基因表达并阻碍集落形成。它通过调节细胞周期蛋白依赖性激酶2和细胞周期蛋白依赖性激酶4的活性，减少视网膜母细胞瘤蛋白磷酸化来实现这一点，降低细胞周期蛋白E水平，增加p21水平，最终影响E2启动子结合因子1和细胞分裂周期2（CDC2）蛋白水平。此外,fisetin对CRC细胞表现出各种作用，包括抑制Y盒结合蛋白1和核糖体S6激酶的磷酸化，促进细胞外信号调节激酶1/2的磷酸化，破坏DNA双链断裂的修复过程。此外，fisetin作为预防和治疗磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α（PIK3CA）突变CRC的辅助疗法，导致磷脂酰肌醇-3激酶（PI3K）表达减少，Ak菌株转化磷酸化，mTOR活动,和具有PIK3CA突变的CRC细胞中的下游靶蛋白。这些发现强调了非塞素在管理CRC方面的多方面潜力，并将其定位为未来治疗发展的有希望的候选人。
