蜡蝉毒素通过活性氧簇克服IL-2Rα信号介导的沃利替酶（vorinostat）耐药在皮肤T细胞淋巴瘤中的作用

Cantharidin overcomes IL-2Rα signaling-mediated vorinostat resistance in cutaneous T-cell lymphoma through reactive oxygen species

Journal for ImmunoTherapy of Cancer

影响因子:10.6

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

DOI: 10.1136/jitc-2024-009099

摘要

沃利替酶（SAHA）是一种组蛋白去乙酰化酶抑制剂，在治疗晚期皮肤T细胞淋巴瘤（CTCL）中显示出临床疗效。然而，只有30-35%的CTCL患者对SAHA有反应，且反应不总是持久。因此，理解这种耐药机制是改善现有治疗效果的迫切需要。本研究旨在识别促成CTCL对SAHA耐药的因素及其缓解策略。研究发现，活性氧（ROS）水平降低导致IL-2受体α（IL-2Rα）的表达增加，从而驱动对SAHA的耐药。我们还证实，蜡蝉毒素通过抑制IL-2Rα相关的信号通路，依赖ROS机制，克服SAHA耐药。机制上，IL-2Rα的快速翻译增加导致在耐药细胞中生成过量的IL-2Rα蛋白，伴随ROS水平下降。与此同时，IL-2R信号的增强表现为IL-2Rβ与IL-2Rγ的相互作用加强，以及JAK/STAT途径的激活和PI3K/AKT/mTOR及MAPK信号的升高。此外，来自传统中药的活性成分蜡蝉毒素显著升高ROS水平，从而抑制IL-2Rα的翻译，抑制下游信号通路，诱导耐药细胞死亡。在体内外实验中，蜡蝉毒素与SAHA协同作用，增强了对SAHA耐药细胞的杀伤作用。本研究揭示了获取性SAHA耐药的分子机制，并提出使用蜡蝉毒素作为潜在策略以克服CTCL治疗耐药性。

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.