State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China.
Sci Signal. 2024 Sep 10;17(853):eadf9388. doi: 10.1126/scisignal.adf9388.
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 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.
结外自然杀伤/T 细胞淋巴瘤（ENKTL）在化放疗后复发率很高。药物耐药性可以由小细胞外囊泡（sEVs）的货物介导。在这里，我们表明肿瘤细胞和血清 sEVs 中跨膜糖蛋白 CD98hc 的高丰度与 ENKTL 进展和耐药性相关。在机制上，聚乙二醇天冬酰胺酶（PEG-asp）治疗是一种针对 ENKTL 的常见疗法，它促进了转录因子 ATF4 向核内易位，在核内，它被 USP1 稳定，并随后增加表达。在肿瘤细胞衍生的 sEVs 中递送的 CD98hc 增加了培养的人 NK 淋巴瘤细胞系、动物模型和难治性/复发 ENKTL 患者样本中的肿瘤细胞增殖和耐药性。此外，同时抑制 USP1 和 EV 分泌协同增强了 PEG-asp 的细胞毒性。这些数据表明，在治疗 ENKTL 中靶向 CD98hc 可能有助于克服耐药性。
