Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.
Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.
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DOI：
10.15252/embj.2021108272
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发表时间：
2022-04-19
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大多数癌症死亡是由耐药疾病的进展引起的，但我们对这种表型的了解有限。癌症治疗产生压力信号，作用于线粒体启动细胞凋亡。从神经母细胞瘤细胞中分离的线粒体暴露于TBID或Bim，这两种死亡效应是由治疗应激激活的。与确诊时获得的患者匹配的肿瘤细胞相比，从复发儿童获得的多药耐药肿瘤细胞显著减少了Bak和Bax的寡聚化和细胞色素c的释放(替代细胞凋亡承诺)。电子显微镜发现，在治疗耐药细胞中，ER-线粒体相关膜(MAM；ER-线粒体接触，ERMC)减少，在治疗敏感肿瘤中，从遗传或生物化学角度减少了MAM的表型耐药。MAMs是将钙离子和生物活性脂质转移到线粒体的平台。在部分耐药细胞中发现钙离子转运减少，但不是所有耐药细胞，抑制钙转运并不能减弱凋亡信号。相反，神经酰胺的合成和转移减少在耐药细胞中是常见的，它的抑制诱导了应激抗性。我们发现内质网-线粒体相关膜是通过神经酰胺转移的细胞凋亡的生理调节因子，并揭示了以前未知的癌症多药耐药机制。内质网线粒体相关膜上神经酰胺的生物合成受损和向线粒体的脂质转移减少了复发肿瘤细胞的凋亡信号，从而导致癌症治疗耐药。
Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug‐resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient‐matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER–mitochondria‐associated membranes (MAMs; ER–mitochondria contacts, ERMCs) in therapy‐resistant cells, and genetically or biochemically reducing MAMs in therapy‐sensitive tumors phenocopied resistance. MAMs serve as platforms to transfer Ca2+ and bioactive lipids to mitochondria. Reduced Ca2+ transfer was found in some but not all resistant cells, and inhibiting transfer did not attenuate apoptotic signaling. In contrast, reduced ceramide synthesis and transfer was common to resistant cells and its inhibition induced stress resistance. We identify ER–mitochondria‐associated membranes as physiologic regulators of apoptosis via ceramide transfer and uncover a previously unrecognized mechanism for cancer multidrug resistance. Impaired ceramide biosynthesis at ER–mitochondria‐associated membranes and lipid transfer into mitochondria decreases apoptotic signaling in relapsed tumor cells, contributing to cancer therapy resistance.