溶酶体逆行运输的激活触发溶酶体-内质网MCSs的TPC1-IP3R1 Ca2+串扰,导致内质网钙的致命消耗。

IF 14.3 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Meng-Yuan Zhu, Yong-Jian Guo, Yu-Qi Zhu, Hong-Zheng Wang, Hai-di Wang, Hong-Yu Chen, Yue-Xin Jiang, Hui Li, Hui Hui
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引用次数: 0

摘要

肿瘤细胞间信号的联系越来越清楚。然而,溶酶体-内质网(ER)相互作用对肿瘤细胞命运的影响仍然相对未知。在急性髓性白血病(AML)中发现了一种新的溶酶体与内质网之间的相互作用,由类黄酮LW-213介导,通过靶向LIMP2(溶酶体整体膜蛋白2型)激活溶酶体修复途径。这导致活化的RAB7A活性,增强溶酶体向核周区域的逆行运输,并增加溶酶体- er膜接触位点(MCSs)的接触。TPC1与IP3R1在这些位点的接近产生了一个集中的钙微结构域,触发Ca2+诱导的Ca2+释放,导致细胞质钙湍流和两种不同的钙潮。这种过量的钙外排耗尽内质网钙储存,引发致命的内质网应激诱导的细胞凋亡。有趣的是,改变HeLa细胞中TPC1的表达水平会影响这些钙动力学,当过表达时复制aml特异性机制。随后的研究使用野生型和limp2敲除THP1细胞的BALB/c异种移植模型,以及ICR小鼠毒性模型,证实了LW-213具有显著的肿瘤生长抑制作用,毒性很小。这些发现强调了靶向溶酶体-内质网钙串音作为一种创新的癌症治疗方法的潜力,强调了LW-213通过调节细胞器相互作用来控制肿瘤细胞命运的治疗前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Activation of Lysosomal Retrograde Transport Triggers TPC1-IP3R1 Ca2+ Crosstalk at Lysosome-ER MCSs Leading to Lethal Depleting of ER Calcium.

Inter-organellar signaling linkages in oncology are increasingly elucidated. However, the impact of lysosome-endoplasmic reticulum (ER) interaction on tumor cell fate remains relatively unexplored. A novel interaction between lysosomes and the ER, mediated by the flavonoid LW-213 through targeting LIMP2 (lysosomal integral membrane protein type 2)to activate a lysosomal repair pathway, is identified in acute myeloid leukemia (AML). This leads to activated RAB7A activity, enhancing lysosomal retrograde transport to the perinuclear region and increasing contact at lysosome-ER membrane contact sites (MCSs). Close proximity of TPC1 to IP3R1 at these sites generates a concentrated calcium microdomain, triggering Ca2+-induced Ca2+ release, which causes cytoplasmic calcium turbulence and two distinct calcium tides. This excessive calcium efflux depletes ER calcium stores, triggering lethal ER stress-induced apoptosis. Interestingly, altering TPC1 expression levels in HeLa cells affected these calcium dynamics, replicating AML-specific mechanisms when overexpressed. Subsequent studies using BALB/c xenograft models with wild-type and LIMP2-knockout THP1 cells, along with ICR mice toxicity models, confirmed LW-213's significant tumor growth inhibition with minimal toxicity. These findings underscore the potential of targeting lysosomal-ER calcium crosstalk as an innovative approach to cancer treatment, highlighting the therapeutic promise of LW-213 in managing tumor cell fate through modulating organellar interactions.

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来源期刊
Advanced Science
Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
18.90
自引率
2.60%
发文量
1602
审稿时长
1.9 months
期刊介绍: Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.
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