Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
J Invest Surg. 2023 Dec;36(1):2266732. doi: 10.1080/08941939.2023.2266732. Epub 2023 Oct 12.
The inhibition of the Hippo pathway through targeting the Yes-associated protein (YAP) presents a novel and promising approach for treating tumors. However, the efficacy of YAP inhibitors in the context of breast cancer (BC) remains incompletely understood. Here, we aimed to investigate the involvement of YAP in BC's metabolic reprogramming and reveal the potential underlying mechanisms. To this end, we assessed the function of verteporfin (VP), a YAP-TEAD complex inhibitor, on the glycolytic activity of BC cells.
We evaluated the expression of YAP by utilizing immunohistochemistry (IHC) in BC patients who have undergone F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) prior to biopsy/surgery. We employed RNA immunoprecipitation (RIP) and fluorescent hybridization (FISH) assays to assess the interaction between mRNA and human antigen R (HuR) in BC cells. The biological importance of YAP in the metabolism and malignancy of BC was evaluated . Finally, the effect of VP on glycolysis was determined by using F-FDG uptake, glucose consumption, and lactate production assays.
Our studies revealed that high expression of YAP was positively correlated with the maximum uptake value (SUV) determined by F-FDG PET/CT imaging in BC samples. Inhibition of YAP activity suppressed glycolysis in BC. The mechanism underlying this phenomenon could be the binding of YAP to HuR, which promotes glycolysis in BC cells. Treatment with VP effectively suppressed glycolysis induced by YAP overexpression in BC cells.
VP exhibited anti-glycolytic effect on BC cells, indicating its therapeutic value as an FDA-approved drug.
通过靶向 Yes 相关蛋白 (YAP) 抑制 Hippo 通路为治疗肿瘤提供了一种新颖且有前景的方法。然而，YAP 抑制剂在乳腺癌 (BC) 中的疗效仍不完全清楚。在这里，我们旨在研究 YAP 在 BC 代谢重编程中的作用，并揭示潜在的机制。为此，我们评估了 YAP 抑制剂 verteporfin (VP) 对 BC 细胞糖酵解活性的影响。
我们利用免疫组织化学 (IHC) 评估了接受 F-氟脱氧葡萄糖正电子发射断层扫描/计算机断层扫描 (F-FDG PET/CT) 检查后行活检/手术的 BC 患者的 YAP 表达。我们采用 RNA 免疫沉淀 (RIP) 和荧光杂交 (FISH) 检测 BC 细胞中 mRNA 与 HuR 的相互作用。评估 YAP 在 BC 代谢和恶性肿瘤中的生物学重要性。最后，通过 F-FDG 摄取、葡萄糖消耗和乳酸生成测定来确定 VP 对糖酵解的影响。
我们的研究表明，YAP 高表达与 BC 样本中 F-FDG PET/CT 成像确定的最大摄取值 (SUV) 呈正相关。抑制 YAP 活性可抑制 BC 中的糖酵解。这种现象的机制可能是 YAP 与 HuR 结合，促进 BC 细胞中的糖酵解。VP 有效抑制了 BC 细胞中 YAP 过表达诱导的糖酵解。
VP 对 BC 细胞表现出抗糖酵解作用，表明其作为 FDA 批准药物的治疗价值。
