Oncogenic HSP90 Facilitates Metabolic Alterations in Aggressive B-cell Lymphomas.
Oncogenic HSP90 Facilitates Metabolic Alterations in Aggressive B-cell Lymphomas.
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DOI：
10.1158/0008-5472.can-21-2734
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发表时间：
2021-10-15
期刊：
影响因子：
11.2
通讯作者：
Cerchietti L
中科院分区：
文献类型：
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作者：
Calvo-Vidal MN;Zamponi N;Krumsiek J;Stockslager MA;Revuelta MV;Phillip JM;Marullo R;Tikhonova E;Kotlov N;Patel J;Yang SN;Yang L;Taldone T;Thieblemont C;Leonard JP;Martin P;Inghirami G;Chiosis G;Manalis SR;Cerchietti L
致癌形式的HSP90在癌细胞中组织和维持功能性的多酶代谢中心，这表明有可能重新利用致癌的HSP90选择性抑制剂来扰乱淋巴瘤细胞的代谢。热休克蛋白90是维持细胞蛋白平衡的关键。在癌细胞中，HSP90也成为稳定多蛋白复合体(包括信号通路和转录复合体)的成核位点。在这里，我们描述了这种形式的HSP90，称为致癌的HSP90，在调节增殖的B细胞淋巴瘤细胞的胞浆代谢途径中所起的作用。致癌的HSP90有助于将代谢酶组织成非膜结合的功能隔间。在保守细胞蛋白稳态的实验条件下，致癌的HSP90协调和维持细胞生物量的能量产生和维持以及细胞外代谢物的分泌所需的多种代谢途径。相反，抑制致癌的HSP90，在没有明显客户蛋白降解的情况下，降低了MYC驱动的代谢重编程的效率。这项研究揭示了致癌的HSP90支持B细胞淋巴瘤细胞和弥漫性大B细胞淋巴瘤患者的代谢，为HSP90抑制剂提供了一种新的活性机制。致癌形式的HSP90在癌细胞中组织和维持功能性的多酶代谢中心，这表明有可能重新利用致癌的HSP90选择性抑制剂来扰乱淋巴瘤细胞的代谢。
The oncogenic form of HSP90 organizes and maintains functional multienzymatic metabolic hubs in cancer cells, suggesting the potential of repurposing oncogenic HSP90 selective inhibitors to disrupt metabolism in lymphoma cells. HSP90 is critical for maintenance of the cellular proteostasis. In cancer cells, HSP90 also becomes a nucleating site for the stabilization of multiprotein complexes including signaling pathways and transcription complexes. Here we described the role of this HSP90 form, referred to as oncogenic HSP90, in the regulation of cytosolic metabolic pathways in proliferating B-cell lymphoma cells. Oncogenic HSP90 assisted in the organization of metabolic enzymes into non-membrane–bound functional compartments. Under experimental conditions that conserved cellular proteostasis, oncogenic HSP90 coordinated and sustained multiple metabolic pathways required for energy production and maintenance of cellular biomass as well as for secretion of extracellular metabolites. Conversely, inhibition of oncogenic HSP90, in absence of apparent client protein degradation, decreased the efficiency of MYC-driven metabolic reprogramming. This study reveals that oncogenic HSP90 supports metabolism in B-cell lymphoma cells and patients with diffuse large B-cell lymphoma, providing a novel mechanism of activity for HSP90 inhibitors. The oncogenic form of HSP90 organizes and maintains functional multienzymatic metabolic hubs in cancer cells, suggesting the potential of repurposing oncogenic HSP90 selective inhibitors to disrupt metabolism in lymphoma cells.