CD98hc promotes drug resistance in extranodal natural killer/T cell lymphoma through tumor cell–derived small extracellular vesicles

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Science Signaling Pub Date : 2024-09-10 DOI:10.1126/scisignal.adf9388

Liming Liao, Ping Yang, Weilong Zhang, Shuyu Yu, Hongmei Jing, Xiaofeng Zheng

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Abstract

Extranodal natural killer/T cell lymphoma (ENKTL) shows a high rate of recurrence after chemoradiotherapy. Drug resistance can be mediated by the cargo of small extracellular vesicles (sEVs). Here, we show that high abundance of the transmembrane glycoprotein CD98hc in tumor cells and serum sEVs was associated with ENKTL progression and drug resistance. Mechanistically, PEGylated-asparaginase (PEG-asp) treatment, a common therapy against ENKTL, promoted the translocation of the transcription factor ATF4 to the nucleus, where it was stabilized by USP1 and subsequently increased CD98hc expression. CD98hc delivered in tumor cell–derived sEVs increased tumor cell proliferation and drug resistance in a cultured human NK lymphoma cell line, animal models, and samples from patients with refractory/relapse ENKTL. Moreover, inhibiting both USP1 and EV secretion synergistically enhanced the cytotoxicity of PEG-asp. These data suggest that targeting CD98hc in the treatment of ENKTL may be beneficial in overcoming drug resistance.

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CD98hc 通过肿瘤细胞衍生的细胞外小泡促进结节外自然杀伤/T 细胞淋巴瘤的耐药性

结节外自然杀伤/T细胞淋巴瘤（ENKTL）在化疗放疗后复发率很高。耐药性可能是由细胞外小泡（sEVs）的载体介导的。在这里，我们发现肿瘤细胞和血清 sEVs 中跨膜糖蛋白 CD98hc 的高丰度与 ENKTL 的进展和耐药性有关。从机理上讲，PEG化天冬酰胺酶（PEG-asp）是治疗ENKTL的一种常用疗法，它能促进转录因子ATF4转位到细胞核，并在细胞核中被USP1稳定，从而增加CD98hc的表达。在培养的人类 NK 淋巴瘤细胞系、动物模型和难治/复发 ENKTL 患者样本中，肿瘤细胞衍生的 sEVs 中的 CD98hc 增加了肿瘤细胞的增殖和耐药性。此外，抑制 USP1 和 EV 分泌可协同增强 PEG-asp 的细胞毒性。这些数据表明，靶向 CD98hc 治疗 ENKTL 可能有利于克服耐药性。

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来源期刊

Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY

CiteScore

9.50

自引率

0.00%

发文量

148

审稿时长

3-8 weeks

期刊介绍： "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.