Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 4104 Biological Sciences Building, 1105 North University Ave., Ann Arbor, MI 48109, USA.
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 4104 Biological Sciences Building, 1105 North University Ave., Ann Arbor, MI 48109, USA.
Cell Rep. 2021 Oct 19;37(3):109848. doi: 10.1016/j.celrep.2021.109848.
During tumor progression, lysosome function is often maladaptively upregulated to match the high energy demand required for cancer cell hyper-proliferation and invasion. Here, we report that mucolipin TRP channel 1 (TRPML1), a lysosomal Ca and Zn release channel that regulates multiple aspects of lysosome function, is dramatically upregulated in metastatic melanoma cells compared with normal cells. TRPML-specific synthetic agonists (ML-SAs) are sufficient to induce rapid (within hours) lysosomal Zn-dependent necrotic cell death in metastatic melanoma cells while completely sparing normal cells. ML-SA-caused mitochondria swelling and dysfunction lead to cellular ATP depletion. While pharmacological inhibition or genetic silencing of TRPML1 in metastatic melanoma cells prevents such cell death, overexpression of TRPML1 in normal cells confers ML-SA vulnerability. In the melanoma mouse models, ML-SAs exhibit potent in vivo efficacy of suppressing tumor progression. Hence, targeting maladaptively upregulated lysosome machinery can selectively eradicate metastatic tumor cells in vitro and in vivo.
在肿瘤进展过程中，溶酶体功能常常失调上调，以匹配癌细胞过度增殖和侵袭所需的高能量需求。在这里，我们报告说，溶酶体 Ca 和 Zn 释放通道 mucolipin 瞬时受体电位通道 1 (TRPML1)在转移性黑色素瘤细胞中与正常细胞相比显著上调。TRPML1 特异性合成激动剂 (ML-SAs) 足以诱导转移性黑色素瘤细胞中快速（数小时内）溶酶体 Zn 依赖性坏死性细胞死亡，而完全不影响正常细胞。ML-SA 引起的线粒体肿胀和功能障碍导致细胞内 ATP 耗竭。虽然在转移性黑色素瘤细胞中药理学抑制或基因沉默 TRPML1 可防止这种细胞死亡，但在正常细胞中过表达 TRPML1 可使 ML-SA 变得脆弱。在黑色素瘤小鼠模型中，ML-SAs 表现出抑制肿瘤进展的强大体内疗效。因此，靶向失调上调的溶酶体机制可以选择性地在体外和体内根除转移性肿瘤细胞。
