The TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 alterations. Using transcriptomic and metabolomic analyses, we showed here that TP53-altered prostate cancer (PCa) exhibits an increased dependency on asparagine and overexpresses asparagine synthetase (ASNS), the enzyme catalyzing the synthesis of asparagine. Mechanistically, loss or mutation of TP53 transcriptionally activated ASNS expression, directly as well as via mTORC1-mediated ATF4 induction, driving de novo asparagine biosynthesis to support CRPC growth. TP53-altered CRPC cells were sensitive to asparagine restriction by knockdown of ASNS or L-asparaginase treatment to deplete the intracellular and extracellular sources of asparagine, respectively, and cell viability was rescued by asparagine addition. Notably, pharmacological inhibition of intracellular asparagine biosynthesis using a glutaminase inhibitor and depletion of extracellular asparagine with L-asparaginase significantly reduced asparagine production and effectively impaired CRPC growth. This study highlights the significance of ASNS-mediated metabolic adaptation as a synthetic vulnerability in CRPC with TP53 alterations, providing a rationale for targeting asparagine production to treat these lethal prostate cancers.

中文翻译：

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天冬酰胺依赖性是 TP53 改变的去势抵抗性前列腺癌中的一个可靶向代谢漏洞


TP53 肿瘤抑制因子在致命的去势抵抗性前列腺癌 (CRPC) 中经常发生改变。然而，迄今为止，还没有专门针对 TP53 改变的有效治疗方法。通过转录组学和代谢组学分析，我们发现 TP53 改变的前列腺癌 (PCa) 对天冬酰胺的依赖性增加，并过度表达天冬酰胺合成酶 (ASNS)，该酶催化天冬酰胺的合成。从机制上讲，TP53 转录激活 ASNS 表达的丢失或突变，直接以及通过 mTORC1 介导的 ATF4 诱导，驱动天冬酰胺从头生物合成，以支持 CRPC 生长。 TP53改变的CRPC细胞对通过敲低ASNS或L-天冬酰胺酶处理来分别耗尽细胞内和细胞外天冬酰胺来源的天冬酰胺限制敏感，并且通过添加天冬酰胺来挽救细胞活力。值得注意的是，使用谷氨酰胺酶抑制剂对细胞内天冬酰胺生物合成的药理学抑制以及使用L-天冬酰胺酶消耗细胞外天冬酰胺显着降低了天冬酰胺的产生并有效地损害了CRPC的生长。这项研究强调了 ASNS 介导的代谢适应作为具有 TP53 改变的 CRPC 中的综合脆弱性的重要性，为靶向天冬酰胺生产来治疗这些致命的前列腺癌提供了理论基础。