Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation
Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation
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DOI：
10.4161/auto.5774
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发表时间：
2008-05-16
期刊：
影响因子：
13.3
通讯作者：
Jaattela, Maria
中科院分区：
文献类型：
--
作者：
Ostenfeld, Marie Stampe;Hoyer-Hansen, Maria;Jaattela, Maria
A（σ-2）受体配体西拉美新在体外诱导癌细胞的溶酶体渗漏和组织蛋白酶依赖性死亡，并在体内显示出有效的抗癌活性。然而，西拉美新使溶酶体不稳定的机制尚不清楚。在这里，我们表明，西拉米新诱导溶酶体pH值的快速上升，随后是溶酶体渗漏和功能障碍。西拉米新在癌细胞溶酶体中的快速积累、其使分离的溶酶体去稳定化的能力以及其作为两亲性胺的化学结构表明其是亲溶酶体洗涤剂。值得注意的是，siramesine还触发自噬体的大量Atg 6-和Atg 7-依赖性积累，其与雷帕霉素复合物1（mTORC 1;自噬抑制剂）的哺乳动物靶标的快速和持续抑制相关。然而，Sirarnesine未能增加长寿命蛋白质的降解速率。因此，自噬体的大量积累可能是由于自噬信号的激活和自噬体周转减少的综合作用。重要的是，自噬体形成的药理学和基于RNA干扰的抑制进一步使癌细胞对西拉米新诱导的细胞毒性敏感。这些数据将西拉米新鉴定为亲溶酶体洗涤剂，其通过直接使溶酶体不稳定来触发细胞死亡，并通过诱导自噬体的积累来进行细胞保护。因此，西拉米新与自噬体形成抑制剂的组合似乎是未来癌症治疗的有希望的方法。
A (sigma-2 receptor ligand siramesine induces lysosornal leakage and cathepsin-dependent death of cancer cells in vitro and displays potent anti-cancer activity in vivo. The mechanism by which siramesine destabilizes lysosomes is, however, unknown. Here, we show that siramesine induces a rapid rise in the lysosomal pH that is followed by lysosomal leakage and dysfunction. The rapid accumulation of siramesine into cancer cell lysosomes, its ability to destabdize isolated lysosomes, and its chemical structure as an amphiphilic amine indicate that it is a lysosomotropic detergent. Notably, siramesine triggers also a substantial Atg6- and Atg7-dependent accumulation of autophagosomes that is associated with a rapid and sustained inhibition of mammalian target of rapamycin complex 1 (mTORC 1; an inhibitor of autophagy). Sirarnesine fails, however, to increase the degradation rate of long-lived proteins. Thus, the massive accumulation of autophagosomes is likely to be due to a combined effect of activation of autophagy signaling and decreased autophagosome turnover. Importantly, pharmacological and RNA interference-based inhibition of autophagosome formation further sensitizes cancer cells to siramesine-induced cytotoxicity, These data identify siramesine as a lysosomotropic detergent that triggers cell death via a direct destabilization of lysosomes and cytoprotection by inducing the accumulation of autophagosomes. Threrefore, the combination of siramesine with inhibitors of autophagosome formation appears as a promising approach for future cancer therapy.