通过自噬受体 Sequestosome 1 (SQSTM1)/p62 介导的纳米药物递送和癌症治疗增强白蛋白结合紫杉醇对人类肺癌和结直肠癌的疗效,ACS Nano

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通过自噬受体 Sequestosome 1 (SQSTM1)/p62 介导的纳米药物递送和癌症治疗增强白蛋白结合紫杉醇对人类肺癌和结直肠癌的疗效
ACS Nano ( IF 15.8 ) Pub Date : 2023-09-22 , DOI: 10.1021/acsnano.3c04739
Yu-Wei Lin, Tzu-Ting Lin, Chien-Hung Chen, Rou-Hsin Wang, Ya-Hui Lin, Tzu-Yen Tseng, Yan-Jun Zhuang, Sheng-Yueh Tang, Yen-Cheng Lin, Jiun-Yu Pang, Rajan Deepan Chakravarthy, Hsin-Chieh Lin, Shey-Cherng Tzou, Jui-I Chao

选择性自噬是一种防御机制，通过处理外来病原体和异常物质来维持细胞稳态。Sequestosome 1 (SQSTM1)/p62 是一种重要的选择性自噬受体，可招募泛素化货物形成自噬体以进行溶酶体降解。Nab-PTX 是一种白蛋白结合紫杉醇纳米颗粒，用于临床癌症治疗。然而，SQSTM1 在调节纳米药物的递送和功效中的作用仍不清楚。在这里，我们表明 SQSTM1 在 Nab-PTX 药物递送和人类肺癌和结直肠癌疗效中发挥着至关重要的作用。Nab-PTX 诱导 SQSTM1 Ser403 磷酸化，从而促进其掺入纳米颗粒的选择性自噬，称为纳米颗粒自噬。Nab-PTX 增加 LC3-II 蛋白表达，从而触发自噬体形成。SQSTM1增强Nab-PTX识别，形成自噬体，被递送至溶酶体进行白蛋白降解，从而释放PTX，诱导有丝分裂灾难和细胞凋亡。SQSTM1 的敲除可在体外和体内下调 Nab-PTX 诱导的有丝分裂灾难、细胞凋亡和肿瘤抑制，并通过 p53 独立途径抑制 Nab-PTX 诱导的 caspase 3 激活。通过转染 SQSTM1-GFP 载体异位表达 SQSTM1 可恢复 Nab-PTX 的药效。重要的是，SQSTM1 在晚期肺癌和结直肠肿瘤中高表达，并且与临床患者的总体生存率较差相关。靶向SQSTM1可能为提高临床癌症治疗中纳米药物的疗效提供重要策略。这项研究证明了 Nab-PTX 通过 SQSTM1 介导的纳米药物输送增强了对人类肺癌和结直肠癌的疗效。

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Enhancing Efficacy of Albumin-Bound Paclitaxel for Human Lung and Colorectal Cancers through Autophagy Receptor Sequestosome 1 (SQSTM1)/p62-Mediated Nanodrug Delivery and Cancer therapy

Selective autophagy is a defense mechanism by which foreign pathogens and abnormal substances are processed to maintain cellular homeostasis. Sequestosome 1 (SQSTM1)/p62, a vital selective autophagy receptor, recruits ubiquitinated cargo to form autophagosomes for lysosomal degradation. Nab-PTX is an albumin-bound paclitaxel nanoparticle used in clinical cancer therapy. However, the role of SQSTM1 in regulating the delivery and efficacy of nanodrugs remains unclear. Here we showed that SQSTM1 plays a crucial role in Nab-PTX drug delivery and efficacy in human lung and colorectal cancers. Nab-PTX induces SQSTM1 phosphorylation at Ser403, which facilitates its incorporation into the selective autophagy of nanoparticles, known as nanoparticulophagy. Nab-PTX increased LC3-II protein expression, which triggered autophagosome formation. SQSTM1 enhanced Nab-PTX recognition to form autophagosomes, which were delivered to lysosomes for albumin degradation, thereby releasing PTX to induce mitotic catastrophe and apoptosis. Knockout of SQSTM1 downregulated Nab-PTX-induced mitotic catastrophe, apoptosis, and tumor inhibition in vitro and in vivo and inhibited Nab-PTX-induced caspase 3 activation via a p53-independent pathway. Ectopic expression of SQSTM1 by transfection of an SQSTM1-GFP vector restored the drug efficacy of Nab-PTX. Importantly, SQSTM1 is highly expressed in advanced lung and colorectal tumors and is associated with poor overall survival in clinical patients. Targeting SQSTM1 may provide an important strategy to improve nanodrug efficacy in clinical cancer therapy. This study demonstrates the enhanced efficacy of Nab-PTX for human lung and colorectal cancers via SQSTM1-mediated nanodrug delivery.

更新日期：2023-09-22

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