Chen Wenqing, Zhang Zhu, Yung Ken Kin-Lam, Ko Joshua Ka-Shun
Department of Biology, Hong Kong Baptist University Hong Kong SAR, China.
Teaching and Research Division, School of Chinese Medicine, Hong Kong Baptist University Hong Kong SAR, China.
Am J Cancer Res. 2022 Jul 15;12(7):3242-3258. eCollection 2022.
Pancreatic ductal adenocarcinoma (PDAC) is a prominent type of pancreatic cancer. We have recently unveiled that the anti-tumor adjuvant calycosin concurrently possesses growth-inhibitory and pro-metastatic potential in PDAC development by regulating transforming growth factor β (TGF-β), which plays dual roles as both tumor suppressor and tumor promoter. Hence, we are interested to explore if the pro-metastatic property of the drug could be attenuated for effective treatment of PDAC. Through network pharmacology, MUC1 had been identified as the most common drug target of herbal constituents (including calycosin) in treating PDAC. Following MUC1 gene silencing, the drug effects of calycosin on migratory activity, growth and metabolic regulation of PDAC cells were assessed by using immunofluorescence microscopy, quantitative real-time polymerase chain reaction (qRT-PCR), Western immunoblotting, co-immunoprecipitation (Co-IP), wound healing assay and flow cytometry, respectively. Through experiments, we further validated the working relationship between MUC1 and TGF-β. Results have elucidated that MUC1 gene suppression could switch off the migratory and pro-metastatic drive of calycosin while retaining its growth-inhibitory power by inducing apoptosis and cell cycle arrest, as well as facilitating autophagy and metabolic regulation. The underlying mechanism involves downregulation of TGF-β that acts via modulation of AMP-activated protein kinase (AMPK), Sirtuin 1 (Sirt1) and fibroblast growth factor 21 (FGF21) signaling. These findings have provided new insights in the safe and target-specific treatment of PDAC.
胰腺导管腺癌（PDAC）是胰腺癌的一种主要类型。我们最近发现，抗肿瘤佐剂毛蕊异黄酮在PDAC发展过程中通过调节转化生长因子β（TGF-β）同时具有生长抑制和促转移潜力，而TGF-β兼具肿瘤抑制因子和肿瘤促进因子的双重作用。因此，我们有兴趣探索该药物的促转移特性是否可以减弱，以有效治疗PDAC。通过网络药理学，已确定粘蛋白1（MUC1）是草药成分（包括毛蕊异黄酮）治疗PDAC时最常见的药物靶点。在MUC1基因沉默后，分别使用免疫荧光显微镜、定量实时聚合酶链反应（qRT-PCR）、蛋白质免疫印迹法、免疫共沉淀（Co-IP）、伤口愈合试验和流式细胞术评估了毛蕊异黄酮对PDAC细胞迁移活性、生长和代谢调节的药物作用。通过实验，我们进一步验证了MUC1与TGF-β之间的作用关系。结果表明，抑制MUC1基因可以消除毛蕊异黄酮的迁移和促转移驱动作用，同时通过诱导凋亡和细胞周期停滞，以及促进自噬和代谢调节来保留其生长抑制能力。潜在机制涉及通过调节AMP激活的蛋白激酶（AMPK）、沉默调节蛋白1（Sirt1）和成纤维细胞生长因子21（FGF21）信号传导来下调TGF-β。这些发现为PDAC的安全和靶向特异性治疗提供了新的见解。
