PO.ET03.02 · 实验与分子治疗
铁转运蛋白介导卵巢癌中的bevacizumab耐药和铁死亡逃逸
Ferroportin mediates bevacizumab resistance and ferroptosis evasion in ovarian cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
适应性耐药仍是癌症治疗中的主要障碍，导致患者预后不良。Bevacizumab（Bev）是卵巢癌（OC）治疗的中流砥柱，然而长期暴露常导致耐药和临床获益减少。因此，理解Bev应答和肿瘤适应背后的机制对改进治疗策略至关重要。为研究这些机制，我们建立了SKOV3 Bev耐药肿瘤模型。RNA-seq分析显示，两个铁死亡抑制基因SLC40A1（倍数变化4.01）和AKR1C2（倍数变化3.81）位于前五个差异表达基因之列，提示铁死亡调控是Bev敏感性的潜在决定因素。与此一致，公共数据集表明高SLC40A1表达的OC细胞对铁死亡耐药，而低SLC40A1与铁死亡易感性相关。体外实验进一步证明SLC40A1水平升高的OC细胞系表现出不稳定铁池减少和铁死亡耐受增强。同样，源自体内模型的Bev耐药OVCAR5和OVCAR8细胞系与亲本对照相比，显示出铁转运蛋白（FPN，即SLC40A1编码的蛋白）的显著上调。对FPN的药理学抑制增加了多个OC细胞系的不稳定铁，而FPN抑制剂VIT-2763显著使Bev耐药细胞对铁死亡敏感（P<0.01）。蛋白质组学分析显示，与未处理对照和耐药肿瘤相比，Bev敏感肿瘤积累了更高水平的多不饱和脂肪酸和更低的谷胱甘肽（P<0.05）。总之，这些发现表明Bev在OC模型中诱导铁死亡，而肿瘤相关的FPN上调使其逃避这种致死性应激。这些数据凸显FPN是克服Bev耐药的有前景治疗靶点。
查看英文原文 English abstract
Adaptive drug resistance remains a major barrier in cancer therapy, driving poor patient outcomes. Bevacizumab (Bev) is a mainstay of ovarian cancer (OC) treatment, yet prolonged exposure frequently leads to resistance and diminished clinical benefit. Understanding the mechanisms underlying Bev response and tumor adaptation is therefore critical for improving therapeutic strategies. To investigate these mechanisms, we established a SKOV3 Bev-resistant tumor model. RNA-seq analysis revealed that two ferroptosis-inhibitory genes, SLC40A1 (fold change 4.01) and AKR1C2 (fold change 3.81) among the top five differentially expressed genes, implicating ferroptosis regulation as a potential determinant of Bev sensitivity. Consistently, public datasets indicate that OC cells with high SLC40A1 expression are resistant to ferroptosis, whereas low SLC40A1 correlates with ferroptosis susceptibility. In vitro experiments further demonstrated that OC cell lines with elevated SLC40A1 levels exhibit reduced labile iron pools and enhanced ferroptosis resistance. Likewise, Bev-resistant OVCAR5 and OVCAR8 cell lines derived from in vivo models showed significant upregulation of ferroportin (FPN), the protein encoded by SLC40A1, compared to parental controls. Pharmacologic inhibition of FPN increased labile iron across multiple OC cell lines, and the FPN inhibitor VIT-2763 markedly sensitized Bev-resistant cells to ferroptosis (P<0.01). Proteiomic profiling revealed that Bev-sensitive tumors accumulate higher levels of polyunsaturated fatty acids and lower glutathione (P<0.05) compared with both untreated controls and resistant tumors. Collectively, these findings indicate that Bev induces ferroptosis in OC models, while tumor-associated upregulation of FPN enables escape from this lethal stress. These data highlight FPN as a promising therapeutic target to overcome Bev resistance.
利益披露 Disclosure
Z. Tang, None..
M. Kim, None.