PO.ET03.03 · 实验与分子治疗
药理学干扰YAP1/TEAD与NF-kappa B的相互作用可抑制前列腺癌
Pharmacological disruption of YAP1/TEAD and NF-kappa B crosstalk suppresses prostate cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
晚期前列腺癌患者预后较差，表现为持续的发病率和死亡率，主要归因于转移性去势抵抗性疾病的发展。近期研究表明，YAP1/TEAD与NF-kappa B通路之间的相互作用对细胞生物学和疾病发病机制至关重要，包括癌症进展、转移和治疗复发。然而，这些致癌通路在前列腺癌中的功能关联仍未得到充分表征。本研究旨在评估两种药理学抑制剂——TED-347（一种选择性YAP1/TEAD抑制剂）和genistein（一种抑制NF-kappa B信号的植物雌激素）——在细胞培养和动物模型中对前列腺癌生长的影响。TED-347和genistein在体外和体内均导致前列腺肿瘤细胞生长的显著减少。在机制上，TED-347和genistein降低了前列腺异种移植瘤中YAP1/TEAD和NF-kappa B/RELA的表达和活性。这些减少伴随着癌症干细胞标志物CD44、CXCR4和ALDH1A1表达的降低（免疫组织化学所示），提示自我更新和肿瘤起始能力受损。用这些药物治疗还增加了CDKN1A的表达，减少了Ki-67染色，并显著升高了裂解型caspase-3水平。值得注意的是，我们的数据还揭示genistein减弱了RELA与TEAD之间的相互作用，这一过程由YAP1介导。这些发现为TED-347和genistein如何抑制前列腺癌细胞生长并诱导细胞死亡提供了机制性见解，将这些药物与降低的肿瘤进展、转移和治疗复发直接联系起来。TED-347和genistein诱导的分子重编程导致凋亡增加和肿瘤活力降低，支持其作为治疗抵抗性前列腺癌治疗策略的潜力，并证明在临床前和临床研究中进一步探索的合理性。
查看英文原文 English abstract
Patients with advanced prostate cancer have poorer prognoses, characterized by persistent morbidity and mortality, primarily due to the development of metastatic castration-resistant disease. Recent studies indicate that crosstalk between the YAP1/TEAD and NF-kappa B pathways is critical for cellular biology and disease pathogenesis, including cancer progression, metastasis, and therapeutic relapse. However, the functional association of these oncogenic pathways in prostate cancer remains insufficiently characterized. This study aims to evaluate the effects of two pharmacological inhibitors: TED-347, a selective YAP1/TEAD inhibitor, and genistein, a phytoestrogen that inhibits NF-kappa B signaling, on prostate cancer growth in both cell culture and animal models. Both TED-347 and genistein result in substantial reductions in prostate tumor cell growth in vitro and in vivo. Mechanistically, TED-347 and genistein decrease the expression and activity of YAP1/TEAD and NF-kappa B/RELA in prostate xenografts. These reductions are accompanied by decreased expression of cancer stem cell markers CD44, CXCR4, and ALDH1A1, as shown by immunohistochemistry, suggesting impaired self-renewal and tumor-initiating capacity. Treatment with these agents also increased CDKN1A expression, reduced Ki-67 staining, and significantly elevated cleaved caspase-3 levels. Notably, our data also reveal that genistein attenuates the interaction between RELA and TEAD, a process mediated by YAP1. These findings provide mechanistic insights into how TED-347 and genistein suppress prostate cancer cell growth and induce cell death, directly linking these agents to reduced tumor progression, metastasis, and therapeutic relapse. The molecular reprogramming induced by TED-347 and genistein leads to increased apoptosis and reduced tumor viability, supporting their potential as therapeutic strategies for treatment-resistant prostate cancer and justifying further investigation in preclinical and clinical settings.
利益披露 Disclosure
S. Unlu, None..
A. M. Dwead, None..
M. M. Al-Mathkour, None..
B. Cinar, None.