Proteomic analysis reveals microvesicles containing NAMPT as mediators of radioresistance in glioma.
Proteomic analysis reveals microvesicles containing NAMPT as mediators of radioresistance in glioma.
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蛋白质组学分析揭示含有 NAMPT 的微泡是神经胶质瘤放射抗性的介质。
DOI：
10.26508/lsa.202201680
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发表时间：
2023-06
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
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作者：
胶质瘤患者经常因为对放射治疗的抵抗而复发。代谢酶NAMPT通过微泡的转移和伴随的NAD水平升高被发现是胶质瘤细胞对辐射产生抗性的机制。侵袭性脑肿瘤胶质瘤（胶质瘤干细胞，GSC）中含有的肿瘤起始细胞促进放射抗性和疾病复发。然而，耐药性的机制还不清楚。在此，我们表明，发生在放射治疗的几个患者来源的GSC线的蛋白质组水平的调节预测其耐药状态，而胶质瘤转录亚型不。我们确定了代谢酶NAMPT通过耐药GSC脱落的微囊泡（NAMPT高MV）转移到辐射敏感细胞介导的辐射抗性机制。NAMPT-高MV在照射后以及在用拟放射性药物或低血清处理后挽救放射敏感性GSC和成纤维细胞的增殖，并增加细胞内NAD（H）水平。最后，我们表明，NAMPT内的MV和其在受体细胞中的酶活性的存在是必要的，以介导这些影响。总的来说，我们证明了GSCs的蛋白质组提供了独特的信息，因为它预测了胶质瘤抵抗放射治疗的能力。此外，我们建立了NAMPT通过MV转移作为一种机制，挽救辐射敏感细胞的辐射后增殖。
Glioma patients often relapse because of resistance to radiation therapy. The transfer of the metabolic enzyme NAMPT via microvesicles and the accompanying elevated levels of NAD are found to be a mechanism by which glioma cells become resistant to radiation. 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.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
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16.6
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56.9
作者：
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通讯作者：
Vogelstein, B
影响因子：
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作者：
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通讯作者：
Cerione RA
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影响因子：
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