线粒体代谢动力学和线粒体钙单向转运蛋白 (MCU) 在 GBM 贝伐珠单抗耐药中的调节作用,Advanced Therapeutics

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线粒体代谢动力学和线粒体钙单向转运蛋白 (MCU) 在 GBM 贝伐珠单抗耐药中的调节作用
Advanced Therapeutics ( IF 3.7 ) Pub Date : 2023-05-05 , DOI: 10.1002/adtp.202300067
Yejin Kim _{1,

2,

3} , Chulhwan Kwak ₄ , Jong Bae Park ₁ , Do‐Hyun Nam _{3,

5} , Hyun‐Woo Rhee ₄ , Sung Soo Kim ₁

Affiliation

适应性氧化磷酸化（OXPHOS）和三羧酸（TCA）循环激活是癌症发生和发展过程中异常能量消耗以获得恶性肿瘤和耐药性所必需的肿瘤微环境。为了阐明胶质母细胞瘤（GBM）线粒体代谢动力学和耐药性相关的分子机制，建立了对贝伐单抗获得性耐药的纵向GBM原位小鼠模型。纵向蛋白质组分析结果显示，OXPHOS、TCA和钙信号基因集在贝伐珠单抗耐药前阶段富集，为耐药阶段做准备。然后，应用 APEX 系统对 GBM 进行生物素化和纯化线粒体基质的蛋白质。细胞器特异性蛋白质组分析表明，线粒体钙单向转运蛋白（MCU）的成孔亚基对于获得贝伐珠单抗耐药性至关重要。此外，缺氧和 MCU 特异性抑制剂 DS16570511 的体外联合作用表明，细胞生长和增殖通过抑制 NF-κB 和 CEBP/β 信号通路而减少。总之，贝伐珠单抗治疗引起的缺氧肿瘤微环境影响线粒体代谢动力学，靶向 MCU 与贝伐珠单抗联合治疗复发性 GBM 是一种有前景的治疗选择。缺氧和 MCU 特异性抑制剂 DS16570511 的体外联合作用表明，细胞生长和增殖通过抑制 NF-κB 和 CEBP/β 信号通路而减少。总之，贝伐珠单抗治疗引起的缺氧肿瘤微环境影响线粒体代谢动力学，靶向 MCU 与贝伐珠单抗联合治疗复发性 GBM 是一种有前景的治疗选择。缺氧和 MCU 特异性抑制剂 DS16570511 的体外联合作用表明，细胞生长和增殖通过抑制 NF-κB 和 CEBP/β 信号通路而减少。总之，贝伐珠单抗治疗引起的缺氧肿瘤微环境影响线粒体代谢动力学，靶向 MCU 与贝伐珠单抗联合治疗复发性 GBM 是一种有前景的治疗选择。

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The Regulatory Roles of Mitochondrial Metabolism Dynamics and Mitochondria Calcium Uniporter (MCU) in Bevacizumab Resistance of GBM

Adapted oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle activations are essential tumor microenvironments for abnormal energy consumption to acquire malignancy and drug resistance during cancer development and progression. To elucidate the molecular mechanism related to the mitochondrial metabolic dynamics and drug resistance in glioblastoma (GBM), a longitudinal GBM orthotopic mouse model with acquired resistance to bevacizumab is established. The longitudinal proteomic analysis results show that OXPHOS, TCA, and calcium signaling gene sets are enriched in the bevacizumab pre-resistance phase for preparing resistance phase. Then, the APEX system to GBM to biotinylate and purify proteins of the mitochondria matrix is applied. The organelle specific proteomic analysis shows that the pore-forming subunits of the mitochondrial calcium uniporter protein (MCU) are essential for acquiring bevacizumab resistance. Additionally, a combination effect of hypoxia and the MCU-specific inhibitor DS16570511 in vitro shows that cell growth and proliferation are reduced via inhibition of NF-κB and CEBP/β signaling pathways. In conclusion, the hypoxic tumor microenvironment induced by bevacizumab treatment affects mitochondrial metabolic dynamics, and targeting MCU is a promising therapeutic option in combination with bevacizumab in recurrent GBM.

更新日期：2023-05-05

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