Lo Dico Alessia, Martelli C, Corsi F, Porro D, Ottobrini L, Bertoli G
Molecular Bioimaging and Physiology (IBFM), CNR, Segrate, Milan, Italy.
NBFC, National Biodiversity Future Center, Palermo, Italy.
Cancer Cell Int. 2023 Jul 5;23(1):133. doi: 10.1186/s12935-023-02969-9.
Breast cancer (BC) is the most common malignancy in women and the second leading cause of cancer-related death; chemoresistance is still a clinical challenge mainly because of the different molecular features of this kind of tumour. Doxorubicin (Doxo) is widely used despite its adverse effects and the common onset of resistance. Chaperone-Mediated Autophagy (CMA) has been identified as an important mechanism through which chemotherapeutics can exert their cytotoxic effects and, in this context, LAMP-2A, the key player of CMA, can be a useful biomarker.
A cohort of patients and breast cancer cells have been screened for Doxo effect and CMA activation by analysing the LAMP-2A level. Molecular silencing has been used to clarify CMA role in BC responsiveness to treatments. Low Doxo doses were combined with other drugs (TMZ or PX-478, a HIF-1α inhibitor) to evaluate their cytotoxic ability and their role in modulating CMA.
In this paper, we showed that CMA is an important mechanism mediating the responsiveness of breast cancer cell to different treatments (Doxo and TMZ, as suggested by triple negative cells that are TMZ-resistant and fails to activate CMA). The LAMP-2A expression level was specific for different cell lines and patient-derived tumour subtypes, and was also useful in discriminating patients for their survival rates. Moreover, molecular silencing or pharmacological blockage of HIF-1α activity reverted BC resistance to TMZ. The combination of low-dose Doxo with TMZ or PX-478 showed that the drug associations have synergistic behaviours.
Here, we demonstrated that CMA activity exerts a fundamental role in the responsiveness to different treatments, and LAMP-2A can be proposed as a reliable prognostic biomarker in breast cancer. In this context, HIF-1α, a potential target of CMA, can also be assessed as a valuable therapeutic target in BC in view of identifying new, more efficient and less toxic therapeutic drug combinations. Moreover, the possibility to combine Doxo with other drugs acting on different but coherent molecular targets could help overcome resistance and open the way to a decrease in the dose of the single drugs.
乳腺癌（BC）是女性中最常见的恶性肿瘤，也是癌症相关死亡的第二大主要原因；化疗耐药性仍然是一个临床挑战，主要是因为这种肿瘤具有不同的分子特征。尽管阿霉素（Doxo）有副作用且常见耐药现象，但仍被广泛使用。伴侣介导的自噬（CMA）已被确定为化疗药物发挥细胞毒性作用的重要机制，在这种情况下，CMA的关键参与者溶酶体相关膜蛋白2A（LAMP-2A）可以作为一个有用的生物标志物。
通过分析LAMP-2A水平，对一组患者和乳腺癌细胞进行了阿霉素效应和CMA激活的筛选。采用分子沉默技术来阐明CMA在乳腺癌对治疗反应中的作用。低剂量阿霉素与其他药物（替莫唑胺（TMZ）或PX-478，一种缺氧诱导因子-1α（HIF-1α）抑制剂）联合使用，以评估它们的细胞毒性能力及其在调节CMA中的作用。
在本文中，我们表明CMA是介导乳腺癌细胞对不同治疗（Doxo和TMZ，如三阴细胞所提示的，三阴细胞对TMZ耐药且无法激活CMA）反应的重要机制。LAMP-2A表达水平对不同细胞系和患者来源的肿瘤亚型具有特异性，也有助于区分患者的生存率。此外，HIF-1α活性的分子沉默或药理学阻断可逆转乳腺癌对TMZ的耐药性。低剂量Doxo与TMZ或PX-478联合使用表明，药物联合具有协同作用。
在此，我们证明CMA活性在对不同治疗的反应中发挥着重要作用，LAMP-2A可被提议作为乳腺癌可靠的预后生物标志物。在这种情况下，鉴于确定新的、更有效且毒性更小的治疗药物组合，CMA的潜在靶点HIF-1α也可被评估为乳腺癌中有价值的治疗靶点。此外，将Doxo与作用于不同但相关分子靶点的其他药物联合使用的可能性有助于克服耐药性，并为降低单一药物剂量开辟道路。
