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醛缩酶B通过抑制G6PD和戊糖磷酸途径抑制肝细胞癌变

原文发布日期：2020-07-06

英文摘要：

摘要翻译：

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文章：

醛缩酶B通过抑制G6PD和戊糖磷酸途径抑制肝细胞癌变

Aldolase B suppresses hepatocellular carcinogenesis by inhibiting G6PD and pentose phosphate pathways

原文发布日期：2020-07-06

英文摘要：

Metabolic reprogramming is a core hallmark of cancer but it remains poorly defined in hepatocellular carcinogenesis (HCC). Here we show that hepatic aldolase B (Aldob) suppresses HCC by directly binding and inhibiting the rate-limiting enzyme in the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD). A stage-dependent decrease of Aldob and increase of G6PD in human tumors are correlated with poor prognosis for patients with HCC. Global or liver-specific Aldob knockout promotes tumorigenesis in mice through enhancing G6PD activity and pentose phosphate pathway metabolism, whereas pharmacological inhibition or genetic knockdown of G6PD suppresses HCC. Consistently, restoration of Aldob in Aldob knockout mice attenuates tumorigenesis. We further demonstrate that Aldob potentiates p53-mediated inhibition of G6PD in an Aldob–G6PD–p53 complex. This scaffolding effect is independent of Aldob enzymatic activity. Together, our study reveals a new mode of metabolic reprogramming in HCC due to the loss of Aldob, suggesting a potential therapeutic strategy for HCC treatment.

摘要翻译：

肝癌中代谢重新编程是一个核心特征，但在肝细胞癌（HCC）中其定义仍不完善。我们发现，肝糖原酶B（Aldob）通过直接结合并抑制葡萄糖-6-磷酸脱氢酶（G6PD），作为影响HCC发生的关键酶，在五碳糖代谢途径中具有关键作用。在人肿瘤组织中，随着疾病进展，Aldob水平呈现阶段性下降、而G6PD水平升高，与HCC患者的预后不良相关。全球或肝区特定的Aldob knockout能够通过促进G6PD活性和肝细胞内五碳糖代谢来增强肿瘤的发生，在小鼠模型中诱导癌变。与此相反，药物抑制剂或基因敲低的G6PD能够抑制HCC的发生。我们进一步发现，在Aldob knockout小鼠中，恢复Aldob能够减弱肿瘤发生。此外，我们还证实了Aldob通过与G6PD以及p53介导的G6PD抑制作用形成一个“脚手架效应”的机制，此效应与Aldob酶活性无关。综上所述，本研究揭示了肝癌中Aldob缺失所导致的代谢重新编程的新模式，为HCC的治疗提供了潜在的 therapeutic策略。