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Abstract：
Cisplatin (CDDP) is a commonly used chemotherapeutic for osteosarcoma (OS) patients, and drug resistance remains as a major hurdle to undermine the treatment outcome. Here, we investigated the potential involvement of FoxG1 and BNIP3 in CDDP resistance of OS cells. FoxG1 and BNIP3 expression levels were detected in the CDDP-sensitive and CDDP-resistant OS tumors and cell lines. Mitophagy was observed through transmission electron microscope analysis. The sensitivity to CDDP in OS cells upon FoxG1 overexpression was examined in cell and animal models. We found that FoxG1 and BNIP3 showed significant downregulation in the CDDP-resistant OS tumor samples and cell lines. CDDP-resistant OS tumor specimens and cells displayed impaired mitophagy. FoxG1 overexpression promoted BNIP3 expression, enhanced mitophagy in CDDP-resistant OS cells, and resensitized the resistant cells to CDDP treatment in vitro and in vivo. Our data highlighted the role of the FoxG1/BNIP3 axis in regulating mitophagy and dictating CDDP resistance in OS cells, suggesting targeting FoxG1/BNIP3-dependent mitophagy as a potential strategy to overcome CDDP resistance in OS.
摘要：
顺铂（CDDP）是骨肉瘤（OS）患者常用的化疗药物，耐药性仍然是破坏治疗结果的主要障碍。这里,我们研究了FoxG1和BNIP3在OS细胞CDDP抵抗中的潜在参与。在CDDP敏感性和CDDP抗性OS肿瘤和细胞系中检测到FoxG1和BNIP3表达水平。通过透射电子显微镜分析观察线粒体自噬。在细胞和动物模型中检查了FoxG1过表达后OS细胞对CDDP的敏感性。我们发现FoxG1和BNIP3在CDDP抗性OS肿瘤样品和细胞系中显示出显著的下调。CDDP抗性OS肿瘤标本和细胞显示线粒体自噬受损。FoxG1过表达促进BNIP3表达，CDDP抗性OS细胞中增强的线粒体自噬，并在体外和体内使耐药细胞对CDDP治疗重新敏感。我们的数据强调了FoxG1/BNIP3轴在调节线粒体自噬和决定OS细胞CDDP抗性中的作用，提示靶向FoxG1/BNIP3依赖性线粒体自噬作为克服OS中CDDP耐药的潜在策略。
