Department of Molecular Medicine, Cornell University, Ithaca, NY, USA.
Department of Neurosurgery, Medical Institute Hokuto Hospital, Hokkaido, Japan.
Life Sci Alliance. 2023 Apr 10;6(6). doi: 10.26508/lsa.202201680. Print 2023 Jun.
Tumor-initiating cells contained within the aggressive brain tumor glioma (glioma stem cells, GSCs) promote radioresistance and disease recurrence. However, mechanisms of resistance are not well understood. Herein, we show that the proteome-level regulation occurring upon radiation treatment of several patient-derived GSC lines predicts their resistance status, whereas glioma transcriptional subtypes do not. We identify a mechanism of radioresistance mediated by the transfer of the metabolic enzyme NAMPT to radiosensitive cells through microvesicles (NAMPT-high MVs) shed by resistant GSCs. NAMPT-high MVs rescue the proliferation of radiosensitive GSCs and fibroblasts upon irradiation, and upon treatment with a radiomimetic drug or low serum, and increase intracellular NAD(H) levels. Finally, we show that the presence of NAMPT within the MVs and its enzymatic activity in recipient cells are necessary to mediate these effects. Collectively, we demonstrate that the proteome of GSCs provides unique information as it predicts the ability of glioma to resist radiation treatment. Furthermore, we establish NAMPT transfer via MVs as a mechanism for rescuing the proliferation of radiosensitive cells upon irradiation.
肿瘤起始细胞存在于侵袭性脑肿瘤神经胶质瘤（神经胶质瘤干细胞，GSCs）中，促进了放射抵抗和疾病复发。然而，其抵抗机制尚不清楚。在此，我们表明，几种患者来源的 GSC 系在接受放射治疗后发生的蛋白质组水平的调节可以预测其抵抗状态，而神经胶质瘤转录亚型则不能。我们发现了一种通过代谢酶 NAMPT 通过耐药 GSCs 分泌的微泡（NAMPT 高 MV）转移到放射敏感细胞的放射抵抗机制。NAMPT 高 MV 可在照射后拯救放射敏感的 GSCs 和成纤维细胞的增殖，并且在接受放射模拟药物或低血清处理后，增加细胞内 NAD（H）水平。最后，我们表明 MV 中 NAMPT 的存在及其在受体细胞中的酶活性对于介导这些效应是必需的。总之，我们证明了 GSCs 的蛋白质组提供了独特的信息，因为它可以预测神经胶质瘤抵抗放射治疗的能力。此外，我们确定了通过 MV 转移 NAMPT 作为在照射后拯救放射敏感细胞增殖的一种机制。
