Ishikawa Chie, Mori Naoki
Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.
Division of Health Sciences, Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, Nishihara, Okinawa, Japan.
Leuk Lymphoma. 2025 Apr;66(4):721-732. doi: 10.1080/10428194.2024.2441875. Epub 2024 Dec 17.
Nrf2 plays a critical role in regulating cytoprotective transcriptional responses and glucose metabolism while also preventing inflammation-induced carcinogenesis. However, Nrf2 can paradoxically promote carcinogenesis. Here, we aimed to elucidate the role of Nrf2 in ATL associated with HTLV-1. HTLV-1-infected T-cell lines exhibited nuclear accumulation of Nrf2. Nrf2 knockdown along with the inhibition of its activity using ML385, decreased cell proliferation and survival. Furthermore, ML385-induced G1 arrest by enhancing γH2AX and p53 expression while downregulating CDK4/6, cyclin D2/E, and c-Myc. Additionally, ML385 triggered caspase-mediated apoptosis by downregulating the expression of anti-apoptotic proteins while upregulating pro-apoptotic proteins. The compound also induced necroptosis, promoted JNK phosphorylation, and inhibited the NF-κB, AP-1, and STAT3/5 signaling. Moreover, ML385 was found to reduce the expression of LDHA, glucose uptake, and the levels of lactate derived from glycolysis. Overall, these results suggest that Nrf2 functions as an oncogene in ATL and may represent a promising therapeutic target.
Nrf2在调节细胞保护转录反应和葡萄糖代谢以及预防炎症诱导的致癌作用中发挥关键作用。然而，Nrf2却可能反常地促进致癌作用。在此，我们旨在阐明Nrf2在与人类嗜T淋巴细胞病毒1型（HTLV-1）相关的成人T细胞白血病（ATL）中的作用。HTLV-1感染的T细胞系表现出Nrf2的核内蓄积。使用ML385抑制Nrf2活性并使其敲低，会降低细胞增殖和存活。此外，ML385通过增强γH2AX和p53表达，同时下调细胞周期蛋白依赖性激酶4/6（CDK4/6）、细胞周期蛋白D2/E和c-Myc，诱导G1期阻滞。另外，ML385通过下调抗凋亡蛋白表达同时上调促凋亡蛋白，触发半胱天冬酶介导的凋亡。该化合物还诱导坏死性凋亡，促进c-Jun氨基末端激酶（JNK）磷酸化，并抑制核因子κB（NF-κB）、激活蛋白1（AP-1）和信号转导子和转录激活子3/5（STAT3/5）信号传导。此外，发现ML385可降低乳酸脱氢酶A（LDHA）的表达、葡萄糖摄取以及糖酵解产生的乳酸水平。总体而言，这些结果表明Nrf2在ATL中作为癌基因发挥作用，可能是一个有前景的治疗靶点。
