Cancer cells have high demands for non-essential amino acids (NEAAs), which are precursors for anabolic and antioxidant pathways that support cell survival and proliferation. It is well-established that cancer cells consume the NEAA cysteine, and that cysteine deprivation can induce cell death; however, the specific factors governing acute sensitivity to cysteine starvation are poorly characterized. Here, we show that that neither expression of enzymes for cysteine synthesis nor availability of the primary precursor methionine correlated with acute sensitivity to cysteine starvation. We observed a strong correlation between efflux of the methionine-derived metabolite methylthioadenosine (MTA) and sensitivity to cysteine starvation. MTA efflux results from genetic deletion of methylthioadenosine phosphorylase (MTAP), which is frequently deleted in cancers. We show that MTAP loss upregulates polyamine metabolism which, concurrently with cysteine withdrawal, promotes elevated reactive oxygen species and prevents cell survival. Our results reveal an unexplored metabolic weakness at the intersection of polyamine and cysteine metabolism.

癌细胞对非必需氨基酸 (NEAA) 有很高的需求，这些氨基酸是支持细胞存活和增殖的合成代谢和抗氧化途径的前体。众所周知，癌细胞会消耗 NEAA 半胱氨酸，而半胱氨酸缺失会导致细胞死亡。然而，控制对半胱氨酸饥饿急性敏感性的具体因素尚不清楚。在这里，我们表明，半胱氨酸合成酶的表达和初级前体甲硫氨酸的可用性均与对半胱氨酸饥饿的急性敏感性无关。我们观察到甲硫氨酸衍生代谢物甲硫腺苷（MTA）的流出与半胱氨酸饥饿的敏感性之间存在很强的相关性。 MTA 外流是由甲基硫腺苷磷酸化酶 ( MTAP ) 基因缺失引起的，该酶在癌症中经常被缺失。我们发现，MTAP 损失会上调多胺代谢，与半胱氨酸戒断同时发生，促进活性氧水平升高并阻止细胞存活。我们的结果揭示了多胺和半胱氨酸代谢交叉点中未探索的代谢弱点。