LNS8801 inhibits Acute Myeloid Leukemia by Inducing the Production of Reactive Oxygen Species and Activating the Endoplasmic Reticulum Stress Pathway.
LNS8801 inhibits Acute Myeloid Leukemia by Inducing the Production of Reactive Oxygen Species and Activating the Endoplasmic Reticulum Stress Pathway.
复制标题
DOI：
10.1158/2767-9764.crc-22-0478
复制
发表时间：
2023-08
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管最近的治疗取得了进展，但成人急性髓性白血病（AML）的5年生存率很低，标准治疗化疗与显著的毒性相关，这突出了对新治疗方法的需求。我们小组和其他人最近的工作证实，G蛋白偶联雌激素受体（GPER）在黑色素瘤和其他实体肿瘤中具有肿瘤抑制作用。我们对来自多种恶性肿瘤的人类癌细胞系进行了初步筛选，发现目前处于早期临床试验的合成GPER药理学激动剂LNS8801促进了人类AML细胞的凋亡。使用人类AML细胞系和原代细胞，我们在临床前体外模型中发现LNS8801抑制人类AML，而不影响正常的单核细胞。尽管GPER在正常和恶性骨髓细胞中广泛表达，但这种癌症特异性lns8801诱导的抑制似乎独立于GPER信号传导。LNS8801主要通过caspase依赖性凋亡途径诱导AML细胞死亡。这与分泌的经典死亡受体配体无关，而是需要诱导活性氧（ROS）和激活内质网（ER）应激反应途径，包括IRE1α。这些研究证明了LNS8801在AML细胞中的新活性，并表明用LNS8801靶向内质网应激可能是一种有效的AML治疗方法。先前的研究表明，LNS8801通过激活GPER抑制癌症，特别是在实体瘤中。本研究表明，LNS8801通过与gper无关的机制抑制AML，包括ROS诱导和内质网激活。
Despite recent therapeutic advances, the 5-year survival rate for adults with acute myeloid leukemia (AML) is poor and standard-of-care chemotherapy is associated with significant toxicity, highlighting the need for new therapeutic approaches. Recent work from our group and others established that the G protein-coupled estrogen receptor (GPER) is tumor suppressive in melanoma and other solid tumors. We performed a preliminary screen of human cancer cell lines from multiple malignancies and found that LNS8801, a synthetic pharmacologic agonist of GPER currently in early phase clinical trials, promoted apoptosis in human AML cells. Using human AML cell lines and primary cells, we show that LNS8801 inhibits human AML in preclinical in vitro models, while not affecting normal mononuclear cells. Although GPER is broadly expressed in normal and malignant myeloid cells, this cancer-specific LNS8801-induced inhibition appeared to be independent of GPER signaling. LNS8801 induced AML cell death primarily through a caspase-dependent apoptosis pathway. This was independent of secreted classical death receptor ligands, and instead required induction of reactive oxygen species (ROS) and activation of endoplasmic reticulum (ER) stress response pathways including IRE1α. These studies demonstrate a novel activity of LNS8801 in AML cells and show that targeting ER stress with LNS8801 may be a useful therapeutic approach for AML. Previous work demonstrated that LNS8801 inhibits cancer via GPER activation, especially in solid tumors. Here we show that LNS8801 inhibits AML via GPER-independent mechanisms that include ROS induction and ER activation.
影响因子：
6.1
作者：
Meyer, Matthias R.;Field, Angela S.;Kanagy, Nancy L.;Barton, Matthias;Prossnitz, Eric R.
通讯作者：
Prossnitz, Eric R.