PO.MCB03.03 · 分子与细胞生物学
通过Hippo-YAP/TAZ-TEAD信号通路探索去势抵抗性前列腺癌的治疗易感性
Exploring the therapeutic vulnerability of castration-resistant prostate cancer via Hippo-YAP/TAZ-TEAD signaling
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：Hippo-YAP/TAZ-TEAD信号轴在包括部分前列腺癌（PCa）在内的多种癌症中常呈上调，然而其在治疗抵抗中的作用仍未完全阐明。本研究探讨了在PCa中靶向YAP/TAZ-TEAD信号的治疗潜力，重点关注雄激素非依赖性及恩杂鲁胺（enzalutamide）抵抗性疾病。
方法：LNCaP、PC3和DU145细胞购自ATCC。恩杂鲁胺抵抗细胞系（LNCaP-ENZR/PCaNO1和C4-2-ENZR/PCaNO2）通过将LNCaP和C4-2细胞用5 µM恩杂鲁胺培养超过6个月生成。mRNA表达通过qRT-PCR定量，蛋白水平通过western blot检测。YAP/TAZ-TEAD抑制剂（GNE-7883、K-975）的抗肿瘤效应通过IncuCyte活细胞成像评估增殖情况；长期存活通过集落形成实验测定。细胞迁移和侵袭分别通过划痕愈合实验和Matrigel transwell实验评估。
结果：雄激素非依赖性PCa细胞（PC3和DU145）与LNCaP细胞相比，YAP/TAZ-TEAD转录靶标显著上调。恩杂鲁胺抵抗性PCaNO1和PCaNO2细胞相对于亲本对照，表现出YAP/TAZ-TEAD靶基因的强烈诱导以及YAP1、TAZ和TEAD蛋白水平升高。恩杂鲁胺抵抗还与PD-L1表达升高相关。药理学抑制YAP/TAZ-TEAD信号在各PCa模型中均显著抑制细胞生长和增殖，并减少集落形成、迁移和侵袭。正在进行的实验旨在评估YAP/TAZ-TEAD抑制对PD-L1调控的影响。
结论：YAP/TAZ-TEAD抑制剂能有效阻断前列腺癌细胞（包括恩杂鲁胺抵抗模型）的增殖和侵袭性。这些发现支持将YAP/TAZ-TEAD信号作为一个有前景的治疗易感靶点，以及作为克服部分晚期前列腺癌治疗抵抗的潜在策略。
查看英文原文 English abstract
Background: The Hippo-YAP/TAZ-TEAD signaling axis is frequently upregulated in many cancers, including subsets of prostate cancer (PCa). However, its role in therapy resistance remains incompletely understood. In this study, we investigated the therapeutic potential of targeting YAP/TAZ-TEAD signaling in PCa, with an emphasis on androgen-independent and enzalutamide-resistant disease.
Methods: LNCaP, PC3, and DU145 cells were obtained from ATCC. Enzalutamide-resistant lines (LNCaP-ENZR/PCaNO1 and C4-2-ENZR/PCaNO2) were generated by culturing LNCaP and C4-2 cells with 5 µM enzalutamide for >6 months. mRNA expression was quantified by qRT-PCR, and protein levels were examined by western blotting. Anti-tumor effects of YAP/TAZ-TEAD inhibitors (GNE-7883, K-975) were assessed using IncuCyte live-cell imaging for proliferation; long-term survival was measured by colony formation assays. Cell migration and invasion were evaluated using scratch-wound healing and Matrigel transwell assays, respectively.
Results: Androgen-independent PCa cells (PC3 and DU145) exhibited marked upregulation of YAP/TAZ-TEAD transcriptional targets compared to LNCaP cells. Enzalutamide-resistant PCaNO1 and PCaNO2 cells displayed strong induction of YAP/TAZ-TEAD target genes and increased YAP1, TAZ, and TEAD protein levels relative to parental controls. Enzalutamide resistance was also associated with elevated PD-L1 expression. Pharmacologic inhibition of YAP/TAZ-TEAD signaling significantly suppressed cell growth and proliferation, and reduced colony formation, migration, and invasion across PCa models. Ongoing experiments are assessing the impact of YAP/TAZ-TEAD inhibition on PD-L1 regulation.
Conclusion: YAP/TAZ-TEAD inhibitors effectively block proliferation and invasiveness of prostate cancer cells, including enzalutamide-resistant models. These findings support YAP/TAZ-TEAD signaling as a promising therapeutic vulnerability and potential strategy to overcome therapy resistance in subsets of advanced prostate cancer.
利益披露 Disclosure
V. Mohan, None..
S. Koul, None..
M. Vatanmakanian, None..
S. Lamichhane, None..
P. K. Jaiswal, None..
H. K. Koul, None.