PO.TB03.03 · 肿瘤生物学
Caveolin-1调节三阴性乳腺癌的干性和化疗敏感性
Caveolin-1 modulates stemness and chemosensitivity in triple negative breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
三阴性乳腺癌（TNBC）是乳腺癌（BC）中侵袭性最强的亚型，其特征为治疗难治性表型、更易发生早期转移以及更差的预后。TNBC中癌症干样细胞（CSC）高表达，导致不良的临床结局。值得注意的是，caveolin-1（CAV-1）——质膜内小窝的一种主要结构蛋白——的上调与TNBC相关。与此一致，Kaplan-Meier生存分析预测，CAV-1高表达的患者其生存显著差于低表达者。同样地，对PDX肿瘤样本的免疫印迹分析揭示了具有高CAV-1表达的肿瘤间差异，支持CAV-1表达失调在TNBC进展中的作用。先前，我们已证明在TNBC的4T1同基因小鼠模型中，CAV-1敲除（Cav-1 KO）通过整合素alpha3减轻了BC向肺的转移。经进一步研究，我们观察到当在小鼠4T1和人SUM159PT细胞中耗竭CAV-1时，SOX2、OCT-4和NANOG等多能转录因子显著下调。我们假设CAV-1通过黏着斑激酶（FAK）/c-Myc信号传导调控TNBC干性。与此一致，CAV-1的耗竭改变了pY397FAK和c-Myc的水平，证实CAV-1依赖性的CSC样特性抑制与FAK/c-Myc信号传导相关。接下来，我们观察到与相应的4T1对照细胞相比，CAV-1 KO细胞对紫杉醇（PTX）表现出增强的化疗敏感性（48h时PTX IC50：Cav-1 KO为24.51nM，4T1为30.82nM）。所观察到的化疗敏感性归因于多药耐药蛋白1（MRP1/ABCC1）和P-糖蛋白（ABCB1）的下调。重要的是，与初始SUM159PT细胞相比，PTX耐药的人Pac200细胞中CAV-1表达显著更高。总之，这些发现表明，CAV-1的缺失损害了主要的药物外排通路并促进化疗敏感性。总体而言，我们的研究提出了CAV-1通过FAK/c-Myc依赖性调节干性通路和ABC外排转运体，在TNBC干性和多药耐药中的一个假定作用。因此，靶向CAV-1提供了一种增强化疗疗效并克服TNBC耐药的治疗策略。由于CAV-1缺乏酶活性或配体结合口袋，小分子靶向可能不是一种可行的方法。因此，通过靶向CAV-1的PROTAC选择性降解Cav-1，提供了一种创新的首创（first-in-class）治疗策略，以消除癌症干性并有效治疗转移性TNBC。
查看英文原文 English abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of BC, characterized by a therapy-refractory phenotype, higher propensity to early metastases, and worse prognosis. TNBC has a high expression of cancer stem-like cells (CSC), contributing to a poor clinical outcome. Notably, an upregulation of caveolin-1 (CAV-1), a major structural protein of caveolae within the plasma membrane, is associated with TNBC. In agreement, the Kaplan-Meier survival analysis predicted that patients with high CAV-1 expression have a significantly worse survival than those with low expression. Consistently, immunoblot analysis of PDX tumor samples revealed inter-tumor variation with high CAV-1 expression, supporting the role of dysregulated CAV-1 expression in TNBC progression. Previously, we have shown that CAV-1 knockout (Cav-1 KO) mitigated BC metastasis to the lungs via integrin alpha3 in a 4T1 syngeneic 4T1-murine model of TNBC. Upon further investigation, we observed a significant downregulation of pluripotent transcription factors such as SOX2, OCT-4, and NANOG when CAV-1 was depleted in mouse 4T1 and human SUM159PT cells. We hypothesized that CAV-1 regulates TNBC stemness through focal adhesion kinase (FAK)/ c-Myc signaling. Consistently, depletion of CAV-1 altered the levels of pY397FAK and c-Myc, confirming CAV-1-dependent suppression of CSC-like traits to be associated with FAK/c-Myc signaling. Next, we observed that CAV-1 KO cells exhibited enhanced chemosensitivity to paclitaxel (PTX) as compared to the corresponding 4T1 control cells (PTX IC 50 : 24.51nM in Cav-1 KO vs 30.82nM in 4T1 at 48h). The observed chemosensitivity was due to the downregulation of multidrug resistant protein 1 (MRP1/ABCC1) and P-glycoprotein (ABCB1). Importantly, CAV-1 expression was significantly higher in PTX-resistant human Pac200 cells as compared to the naïve SUM159PT cells. Collectively, these findings indicate that CAV-1 loss impairs major drug efflux pathways and promotes chemosensitivity. Overall, our study proposed a putative role for CAV-1 in TNBC stemness and multidrug resistance through FAK/c-Myc dependent modulation of the stemness pathway and ABC efflux transporters. Therefore, targeting CAV-1 provides a therapeutic strategy to enhance chemotherapy efficacy and overcome drug resistance in TNBC. Since CAV-1 lacks enzymatic activity or ligand-binding pockets, small-molecule targeting may not be a feasible approach. Hence, selective degradation of Cav-1 by (CAV-1)targeting PROTAC offers an innovative first-in-class therapeutic strategy to abrogate cancer stemness and effectively treat metastatic TNBC.
利益披露 Disclosure
S. Pokharel, None..
D. P. Singh, None..
S. Thota, None..
R. Begum, None..
S. Srivastava, None..
Y. Yo, None..
S. Su, None..
D. Raman, None..
J. Francis, None.