The autophagy-mediated lysosomal pathway plays an important role in conferring stress tolerance to tumor cells during cellular stress such as increased metabolic demands. Thus, targeted disruption of this function and inducing lysosomal cell death have been proved to be a useful cancer therapeutic approach. In this study, we reported that octyl syringate (OS), a novel phenolic derivate, was preferentially cytotoxic to various cancer cells but was significantly less cytotoxic to non-transformed cells. Treatment with OS resulted in non-apoptotic cell death in a caspase-independent manner. Notably, OS not only enhanced accumulation of autophagic substrates, including lapidated LC3 and sequestosome-1, but also inhibited their degradation via an autophagic flux. In addition, OS destabilized the lysosomal function, followed by the intracellular accumulation of the non-digestive autophagic substrates such as bovine serum albumin and stress granules. Furthermore, OS triggered the release of lysosomal enzymes into the cytoplasm that contributed to OS-induced non-apoptotic cell death. Finally, we demonstrated that OS was well tolerated and reduced tumor growth in mouse xenograft models. Taken together, our study identifies OS as a novel anticancer agent that induces lysosomal destabilization and subsequently inhibits autophagic flux and further supports development of OS as a lysosome-targeting compound in cancer therapy.

Graphical abstract

• Octyl syringate, a phenolic derivate, is preferentially cytotoxic to various cancer cells.

• Octyl syringate destabilizes the lysosomal function.

• Octyl syringate blocks the autophagic flux.

• Octyl syringate is a potential candidate compound for cancer therapy.

中文翻译：

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丁香酸辛酯优先通过溶酶体膜透化和自噬通量抑制对癌细胞产生细胞毒性

自噬介导的溶酶体途径在细胞应激（例如代谢需求增加）期间赋予肿瘤细胞应激耐受性方面起着重要作用。因此，靶向破坏该功能并诱导溶酶体细胞死亡已被证明是一种有用的癌症治疗方法。在这项研究中，我们报道了一种新型酚类衍生物丁香酸辛酯 (OS) 对各种癌细胞具有优先细胞毒性，但对未转化细胞的细胞毒性明显较低。OS 处理导致半胱天冬酶非依赖性方式的非凋亡性细胞死亡。值得注意的是，OS 不仅增强了自噬底物（包括 lapidated LC3 和 sequestosome-1）的积累，而且还通过自噬通量抑制了它们的降解。此外，OS 使溶酶体功能不稳定，随后是非消化性自噬底物如牛血清白蛋白和应激颗粒的细胞内积累。此外，OS 触发溶酶体酶释放到细胞质中，从而导致 OS 诱导的非凋亡性细胞死亡。最后，我们证明了 OS 在小鼠异种移植模型中具有良好的耐受性并减少了肿瘤生长。综上所述，我们的研究将 OS 确定为一种新型抗癌剂，可诱导溶酶体不稳定并随后抑制自噬通量，并进一步支持将 OS 开发为癌症治疗中的溶酶体靶向化合物。我们证明了 OS 在小鼠异种移植模型中具有良好的耐受性并减少了肿瘤生长。综上所述，我们的研究将 OS 确定为一种新型抗癌剂，可诱导溶酶体不稳定并随后抑制自噬通量，并进一步支持将 OS 开发为癌症治疗中的溶酶体靶向化合物。我们证明了 OS 在小鼠异种移植模型中具有良好的耐受性并减少了肿瘤生长。综上所述，我们的研究将 OS 确定为一种新型抗癌剂，可诱导溶酶体不稳定并随后抑制自噬通量，并进一步支持将 OS 开发为癌症治疗中的溶酶体靶向化合物。

图形概要

• 丁香酸辛酯是一种酚类衍生物，对多种癌细胞具有优先细胞毒性。

• Octyl syringate 使溶酶体功能不稳定。

• Octyl syringate 阻断自噬通量。

• Octyl syringate 是一种潜在的癌症治疗候选化合物。