文章：

靶向S100A9蛋白可影响mTOR-ER应激信号通路并增加急性髓系白血病对维奈托克的敏感性

Targeting S100A9 protein affects mTOR-ER stress signaling and increases venetoclax sensitivity in Acute Myeloid Leukemia

原文发布日期：2023-12-18

DOI: 10.1038/s41408-023-00962-z

类型: Article

开放获取: 是

英文摘要：

Acute Myeloid Leukemia (AML) is a heterogeneous disease with limited treatment options and a high demand for novel targeted therapies. Since myeloid-related protein S100A9 is abundantly expressed in AML, we aimed to unravel the therapeutic impact and underlying mechanisms of targeting both intracellular and extracellular S100A9 protein in AML cell lines and primary patient samples. S100A9 silencing in AML cell lines resulted in increased apoptosis and reduced AML cell viability and proliferation. These therapeutic effects were associated with a decrease in mTOR and endoplasmic reticulum stress signaling. Comparable results on AML cell proliferation and mTOR signaling could be observed using the clinically available S100A9 inhibitor tasquinimod. Interestingly, while siRNA-mediated targeting of S100A9 affected both extracellular acidification and mitochondrial metabolism, tasquinimod only affected the mitochondrial function of AML cells. Finally, we found that S100A9-targeting approaches could significantly increase venetoclax sensitivity in AML cells, which was associated with a downregulation of BCL-2 and c-MYC in the combination group compared to single agent therapy. This study identifies S100A9 as a novel molecular target to treat AML and supports the therapeutic evaluation of tasquinimod in venetoclax-based regimens for AML patients.
 

摘要翻译： 

急性髓系白血病（AML）是一种异质性疾病，治疗选择有限，对新型靶向疗法需求迫切。鉴于髓系相关蛋白S100A9在AML中高表达，本研究旨在揭示靶向细胞内和细胞外S100A9蛋白对AML细胞系及原代患者样本的治疗作用及其潜在机制。在AML细胞系中沉默S100A9可导致细胞凋亡增加，并降低AML细胞活力与增殖能力。这些治疗效果与mTOR信号通路和内质网应激信号减弱相关。使用临床可用的S100A9抑制剂他喹莫德也能观察到对AML细胞增殖和mTOR信号通路的类似抑制作用。值得注意的是，虽然siRNA介导的S100A9靶向干预同时影响细胞外酸化和线粒体代谢，但他喹莫德仅影响AML细胞的线粒体功能。最后，我们发现靶向S100A9能显著增强AML细胞对维奈托克的敏感性，联合治疗组与单药治疗组相比，BCL-2和c-MYC表达下调。本研究确立了S100A9作为治疗AML的新分子靶点，并支持将他喹莫德纳入基于维奈托克的联合方案进行临床疗效评估。

原文链接：

Targeting S100A9 protein affects mTOR-ER stress signaling and increases venetoclax sensitivity in Acute Myeloid Leukemia