Autophagy plays a pivotal role in the development and prevention of numerous diseases, and the induction of autophagy is regarded as a potential therapeutic approach for intractable diseases. In this study, the induction of autophagy by methylated β-cyclodextrins (Me-β-CDs)-threaded acid-labile polyrotaxane (Me-PRX) that can release the threaded Me-β-CDs in response to acidic pH in lysosomes was investigated. We hypothesized that the Me-β-CDs released from the Me-PRX interact with the membrane of organelles and cause autophagy. The Me-PRX preferentially accumulated in endoplasmic reticulum (ER) and caused ER stress, which was confirmed by gene expression analysis and the expression of an ER stress-marker protein. Accompanying the ER stress, cells treated with Me-PRX showed autophagy, which was not observed in cells treated with non-labile Me-PRX, other chemically modified PRXs, or free Me-β-CD. Furthermore, the Me-PRX treatment induced autophagic cell death and caused cell death even in apoptosis-resistant cells. Overall, this study demonstrates that the acid-labile Me-PRX induces ER stress-mediated autophagic cell death, and the Me-PRX would be a promising candidate to induce effective cell death in apoptosis-resistant malignant tumors.

自噬在多种疾病的发生和预防中起着举足轻重的作用，自噬的诱导被认为是顽固性疾病的一种潜在治疗方法。在这项研究中，研究了甲基化的β-环糊精（Me-β-CDs）-螺纹的酸不稳定的聚轮烷（Me-PRX）诱导的自噬，该蛋白可以响应溶酶体中的酸性pH释放螺纹的Me-β-CD。 。我们假设从Me-PRX释放的Me-β-CD与细胞器的膜相互作用并引起自噬。Me-PRX优先积累在内质网（ER）中并引起ER应激，这已通过基因表达分析和ER应激标记蛋白的表达得到证实。伴随内质网应激，用Me-PRX处理的细胞表现出自噬作用，而在用非不稳定Me-PRX处理的细胞中则未观察到自噬作用，其他化学修饰的PRX或游离的Me-β-CD。此外，Me-PRX处理诱导自噬细胞死亡，甚至在抗凋亡细胞中也引起细胞死亡。总体而言，这项研究表明，酸不稳定的Me-PRX诱导内质网应激介导的自噬细胞死亡，而Me-PRX将是在抗凋亡的恶性肿瘤中诱导有效细胞死亡的有前途的候选者。