Patients with mutated TP53 have been identified as having comparatively poor outcomes compared to those retaining wild-type p53 in many cancers, including squamous cell carcinomas of the head and neck (SCCHN). We have examined the role of p53 in regulation of metabolism in SCCHN cells and find that loss of p53 function determines the Warburg effect in these cells. Moreover, this metabolic adaptation to loss of p53 function creates an Achilles' heel for tumour cells that can be exploited for potential therapeutic benefit. Specifically, cells lacking normal wild-type p53 function, whether through mutation or RNAi-mediated downregulation, display a lack of metabolic flexibility, becoming more dependent on glycolysis and losing the ability to increase energy production from oxidative phosphorylation. Thus, cells that have compromised p53 function can be sensitised to ionizing radiation by pre-treatment with a glycolytic inhibitor. These results demonstrate the deterministic role of p53 in regulating energy metabolism and provide proof of principle evidence for an opportunity for patient stratification based on p53 status that can be exploited therapeutically using current standard of care treatment with ionising radiation.

中文翻译：

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头颈癌细胞中的 TP53 突变决定了 Warburg 表型转换，从而产生代谢脆弱性和分层疗法的治疗机会。


与保留野生型 p53 的患者相比，在许多癌症（包括头颈鳞状细胞癌 (SCCHN)）中，携带突变 TP53 的患者的预后相对较差。我们研究了 p53 在 SCCHN 细胞代谢调节中的作用，发现 p53 功能的丧失决定了这些细胞中的 Warburg 效应。此外，这种对 p53 功能丧失的代谢适应为肿瘤细胞带来了致命弱点，可利用该弱点获得潜在的治疗益处。具体来说，缺乏正常野生型 p53 功能的细胞，无论是通过突变还是 RNAi 介导的下调，都会表现出缺乏代谢灵活性，变得更加依赖糖酵解，并失去通过氧化磷酸化增加能量产生的能力。因此，通过用糖酵解抑制剂预处理，可以使 p53 功能受损的细胞对电离辐射敏感。这些结果证明了 p53 在调节能量代谢中的决定性作用，并为基于 p53 状态进行患者分层的机会提供了原则证据，可以使用当前的电离辐射护理标准进行治疗。