Experimental Oncology Laboratory, IRCCS Istituto Ortopedico Rizzoli, Bologna, 40136, Italy.
Alma Mater Institute On Healthy Planet - Alma Healthy Planet, University of Bologna, Bologna, Italy.
Cell Oncol (Dordr). 2022 Dec;45(6):1237-1251. doi: 10.1007/s13402-022-00713-5. Epub 2022 Sep 23.
The relevance of the subfamily A members of ATP-binding cassette (ABCA) transporters as biomarkers of risk and response is emerging in different tumors, but their mechanisms of action have only been partially defined. In this work, we investigated their role in Ewing sarcoma (EWS), a pediatric cancer with unmet clinical issues.
The expression of ABC members was evaluated by RT-qPCR in patients with localized EWS. The correlation with clinical outcome was established in different datasets using univariate and multivariate statistical methods. Functional studies were conducted in cell lines from patient-derived xenografts (PDXs) using gain- or loss-of-function approaches. The impact of intracellular cholesterol levels and cholesterol lowering drugs on malignant parameters was considered.
We found that ABCA6, which is usually poorly expressed in EWS, when upregulated became a prognostic factor of a favorable outcome in patients. Mechanistically, high expression of ABCA6 impaired cell migration and increased cell chemosensitivity by diminishing the intracellular levels of cholesterol and by constitutive IGF1R/AKT/mTOR expression/activation. Accordingly, while exposure of cells to exogenous cholesterol increased AKT/mTOR activation, the cholesterol lowering drug simvastatin inhibited IGF1R/AKT/mTOR signaling and prevented Ser166 phosphorylation of MDM2. This, in turn, favored p53 activation and enhanced pro-apoptotic effects of doxorubicin.
Our study reveals that ABCA6 acts as tumor suppressor in EWS cells via cholesterol-mediated inhibition of IGF1R/AKT/MDM2 signaling, which promotes the pro-apoptotic effects of doxorubicin and reduces cell migration. Our findings also support a role of ABCA6 as biomarker of EWS progression and sustains its assessment for a more rational use of statins as adjuvant drugs.
ATP 结合盒（ABC）转运体的亚家族 A 成员作为不同肿瘤风险和反应的生物标志物的相关性正在出现，但它们的作用机制仅部分定义。在这项工作中，我们研究了它们在尤文肉瘤（EWS）中的作用，这是一种具有未满足临床需求的儿科癌症。
通过 RT-qPCR 评估局部 EWS 患者中 ABC 成员的表达。使用单变量和多变量统计方法在不同的数据集上建立与临床结果的相关性。使用功能获得或功能丧失方法在源自患者衍生的异种移植（PDX）的细胞系中进行功能研究。考虑了细胞内胆固醇水平和降低胆固醇药物对恶性参数的影响。
我们发现，通常在 EWS 中表达不佳的 ABCA6 上调后成为患者预后良好的预后因素。从机制上讲，ABCA6 的高表达通过减少细胞内胆固醇水平和组成性 IGF1R/AKT/mTOR 表达/激活来损害细胞迁移并增加细胞化学敏感性。因此，虽然细胞暴露于外源性胆固醇会增加 AKT/mTOR 激活，但降低胆固醇的药物辛伐他汀抑制 IGF1R/AKT/mTOR 信号传导并防止 MDM2 的 Ser166 磷酸化。这反过来又有利于 p53 激活并增强阿霉素的促凋亡作用。
我们的研究表明，ABCA6 通过胆固醇介导的 IGF1R/AKT/MDM2 信号抑制在 EWS 细胞中发挥肿瘤抑制作用，这促进了阿霉素的促凋亡作用并减少了细胞迁移。我们的研究结果还支持 ABCA6 作为 EWS 进展的生物标志物的作用，并支持评估他汀类药物作为辅助药物的更合理使用。
