Cantharidin克服了皮肤T细胞淋巴瘤中的IL-2Rα信号传导介导的Vorinostat耐药性通过活性氧
Cantharidin overcomes IL-2Rα signaling-mediated vorinostat resistance in cutaneous T-cell lymphoma through reactive oxygen species
影响因子:10.60000
分区:医学1区 Top / 免疫学1区 肿瘤学2区
发表日期:2024 Jul 14
作者:
Man Zhu, Wenjun Tang, Xiaoyu Tang, Zeren Zhu, Yina Jiang, Ammar Sarwar, Hongmei Zhang, Dake Chu, Zixi Zhang, Yanmin Zhang
摘要
Vorinostat（SAHA）是一种组蛋白脱乙酰基酶抑制剂，已显示出针对晚期皮肤T细胞淋巴瘤（CTCL）的临床功效。但是，只有一部分CTCL患者（30-35％）对SAHA做出反应，并且反应并不总是可持续的。 Thus, understanding the mechanisms underlying evasive resistance in this cancer is an unmet medical need to improve the efficacy of current therapies.This study aims to identify factors contributing to resistance against SAHA in CTCL and ways to mitigate it.In this study, we demonstrated that attenuated reactive oxygen species (ROS) induces the expression of interleukin (IL)-2Rα, one of the IL-2 receptors, which drives resistance到CTCL的Saha。我们还确定cantharidin可以通过通过ROS依赖性方式阻止IL-2Rα相关的信号来克服对CTCL的抗性。从机械上讲，IL-2Rα的加速翻译导致耐药CTCL中ROS水平降低的导致过度IL-2Rα蛋白形成。同时，通过与IL-2Rβ与IL-2Rγ和JANUS激酶/信号传感器以及转录分子的激活剂的增强相互作用以及蛋白激酶B（AKT）/MTOR/MTOR的表达增加，可以证明放大的IL-2R信号证明了扩增的IL-2R信号。此外，在传统中药中使用的Mylabris的活性成分Cantharidin显着提高了ROS水平，从而限制了IL-2Rα的翻译，从而导致抑制了抗SAHA耐药细胞的下游途径。还发现Cantharidin通过IL-2R信号在体外和体内触发SAHA和SAHA耐药细胞死亡协同作用。我们的发现是Cantharidin在治疗CTCL中的治疗潜力的基础。
Abstract
Vorinostat (SAHA) is a histone deacetylase inhibitor that has shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, only a subset of patients with CTCL (30-35%) respond to SAHA and the response is not always sustainable. Thus, understanding the mechanisms underlying evasive resistance in this cancer is an unmet medical need to improve the efficacy of current therapies.This study aims to identify factors contributing to resistance against SAHA in CTCL and ways to mitigate it.In this study, we demonstrated that attenuated reactive oxygen species (ROS) induces the expression of interleukin (IL)-2Rα, one of the IL-2 receptors, which drives resistance to SAHA in CTCL. We also determined that cantharidin could overcome SAHA resistance to CTCL by blocking IL-2Rα-related signaling via ROS-dependent manner. Mechanistically, accelerated translation of IL-2Rα contributes to excessive IL-2Rα protein formation as a result of reduced ROS levels in SAHA-resistant CTCL. At the same time, amplified IL-2R signals are evidenced by strengthened interaction of IL-2Rβ with IL-2Rγ and Janus kinase/signal transducer and activator of transcription molecules, and by increased expression of protein kinase B (AKT)/mTOR and mitogen-activated protein kinase signaling. Moreover, cantharidin, an active constituent of Mylabris used in traditional Chinese medicine, markedly increased ROS levels, and thereby restrained IL-2Rα translation, resulting in suppression of downstream pathways in SAHA-resistant cells. Cantharidin is also found to synergize with SAHA and triggers SAHA-resistant cell death via IL-2R signaling both in vitro and in vivo.Our study uncovers a novel molecular mechanism of acquired SAHA resistance and also suggests that using cantharidin is a potential approach to overcome CTCL therapy resistance. Our findings underlie the therapeutic potential of cantharidin in treating CTCL.