ClC-3 silencing mediates lysosomal acidification arrest and autophagy inhibition to sensitize chemo-photothermal therapy.
ClC-3 silencing mediates lysosomal acidification arrest and autophagy inhibition to sensitize chemo-photothermal therapy.
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DOI：
10.1016/j.ijpharm.2022.122297
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发表时间：
2022-10
影响因子：
5.8
通讯作者：
Hongyu Zhang;Lanxin Meng;Lei Yin;Taojian Fan;Lan Yu;Shichao Han;Lixia Wang;Weiyuan Liang;Xiaoli Yang;Shiguo Sun
中科院分区：
文献类型：
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作者：
Hongyu Zhang;Lanxin Meng;Lei Yin;Taojian Fan;Lan Yu;Shichao Han;Lixia Wang;Weiyuan Liang;Xiaoli Yang;Shiguo Sun
保护性自噬可被化疗（CT）和光热治疗（PTT）等外部刺激激活，导致肿瘤抵抗。作为自噬的关键亚细胞，溶酶体功能障碍对自噬抑制至关重要。此外，溶酶体药物隔离增强了基本耐药性，如阿霉素（DOX），它被困在远离其靶部位，即细胞核的地方。此外，大多数纳米药物传递系统被内化为溶酶体降解，这进一步导致DOX耐药。溶酶体在耐药机制中是一个重要的细胞器，其酸化阻滞为同时抑制自噬和溶酶体药物隔离提供了一种潜在的策略。氯离子通道-3 （ClC-3）蛋白被认为是一种重要的Cl−-H+转运蛋白，用于维持各种人类细胞溶酶体的低pH值。本文构建了基于黑磷的治疗纳米平台BP-A-S@D，并以HeLa细胞为模型验证ClC-3对肿瘤溶酶体酸化和自噬调节的影响。因此，ClC-3沉默不仅抑制保护性自噬以使化学光热疗法变得敏感，还通过抑制溶酶体酸化来抑制DOX抗性。因此，ClC-3沉默可以同时抑制自噬和溶酶体药物隔离，从而提高抗肿瘤效率。
Protective autophagy can be activated by external stimuli such as chemotherapy (CT) and photothermal therapy (PTT), leading to tumour resistance. As a key subcellular for autophagy, lysosomal dysfunction is crucial for autophagy suppression. Furthermore, lysosomal drug sequestration enhances basic drug resistance such as doxorubicin (DOX), which is trapped away from its target site, namely, the nucleus. Moreover, most of nanodrug delivery systems are internalised to lysosome for degradation, which further leads to DOX resistance. Lysosome serves as an essential organelle in drug resistance mechanisms, whose acidification arrest provides a potential strategy to inhibit autophagy and lysosomal drug sequestration simultaneously. The chloride channel-3 (ClC-3) protein is known as an important Cl−-H+transporter to maintain lysosomal pH at low values of various human cells. Herein, a black phosphorus-based theranostic nanoplatform of BP-A-S@D is constructed, and HeLa cells are used as a model to verify the effect of ClC-3 on tumour lysosomal acidification and autophagy regulation. Consequently, ClC-3 silencing inhibits not only protective autophagy to sensitise chemo-photothermal therapy, but also DOX resistance by suppressing lysosomal acidification. Therefore, ClC-3 silencing could simultaneously inhibit autophagy and lysosomal drug sequestration to improve anti-tumour efficiency.