Abstract：
Pancreatic adenocarcinoma (PDAC) is one of the most lethal malignant tumors with an urgent need for precision medicine strategies. The present study seeks to assess the antitumor effects of fisetin, and characterize its impact on PDAC. Multi-omic approaches include proteomic, transcriptomic, and metabolomic analyses. Further validation includes the assessment of mitochondria-derived reactive oxygen species (mtROS), mitochondrial membrane potential, as well as ATP generation. Molecular docking, immunoprecipitation, and proximity ligation assay were used to detect the interactions among fiseitn, superoxide dismutase 2 (SOD2), and sirtuin 2 (SIRT2). We showed that fisetin disrupted mitochondrial homeostasis and induced SOD2 acetylation in PDAC. Further, we produced site mutants to determine that fisetin-induced mtROS were dependent on SOD2 acetylation. Fisetin inhibited SIRT2 expression, thus blocking SOD2 deacetylation. SIRT2 overexpression could impede fisetin-induced SOD2 acetylation. Additionally, untargeted metabolomic analysis revealed an acceleration of folate metabolism with fisetin. Collectively, our findings suggest that fisetin disrupts mitochondrial homeostasis, eliciting an important cancer-suppressive role; thus, fisetin may serve as a promising therapeutic for PDAC.
摘要：
胰腺腺癌（PDAC）是最致命的恶性肿瘤之一，迫切需要精准医疗策略。本研究旨在评估非塞素的抗肿瘤作用，并表征其对PDAC的影响。多组学方法包括蛋白质组学，转录组，和代谢组学分析。进一步的验证包括评估线粒体衍生的活性氧（mtROS），线粒体膜电位，以及ATP生成。分子对接,免疫沉淀,和邻近连接试验用于检测FISEITN之间的相互作用，超氧化物歧化酶2（SOD2），和沉默蛋白2（SIRT2）。我们发现非塞素破坏线粒体稳态并诱导PDAC中的SOD2乙酰化。Further,我们产生了位点突变体以确定非瑟酮诱导的mtROS依赖于SOD2乙酰化。Fisetin抑制SIRT2表达，从而阻断SOD2脱乙酰化。SIRT2过表达可阻碍非瑟酮诱导的SOD2乙酰化。此外,非靶向代谢组学分析显示，非瑟酮可加速叶酸代谢。总的来说，我们的研究结果表明，非塞素破坏线粒体稳态，引发重要的癌症抑制作用；因此，Fisetin可能是PDAC的一种有前途的治疗方法。
