The de novo serine synthesis pathway is upregulated in many cancers. However, even cancer cells with increased serine synthesis take up large amounts of serine from the environment¹, and we confirm that exogenous serine is needed for maximal proliferation of these cells. Here we show that even when enzymes in the serine synthesis pathway are genetically upregulated, the demand for oxidized NAD⁺ constrains serine synthesis, rendering serine-deprived cells sensitive to conditions that decrease the cellular NAD⁺/NADH ratio. Further, purine depletion is a major consequence of reduced intracellular serine availability, particularly when NAD⁺ regeneration is impaired. Thus, cells rely on exogenous serine consumption to maintain purine biosynthesis. In support of this explanation, providing exogenous purine nucleobases, or increasing NAD⁺ availability to facilitate de novo serine and purine synthesis, rescues maximal proliferation even in the absence of extracellular serine. Together, these data indicate that NAD⁺ is an endogenous limitation for cancer cells to synthesize the serine needed for purine production to support rapid proliferation.

从头丝氨酸合成途径在许多癌症中上调。然而，即使是丝氨酸合成增加的癌细胞也会从环境中摄取大量丝氨酸¹，我们证实这些细胞的最大增殖需要外源丝氨酸。在这里我们表明，即使丝氨酸合成途径中的酶被基因上调，对氧化 NAD ⁺的需求也会限制丝氨酸合成，使丝氨酸缺乏的细胞对降低细胞 NAD ⁺ /NADH 比率的条件敏感。此外，嘌呤消耗是细胞内丝氨酸可用性降低的主要结果，特别是当 NAD ⁺再生受损。因此，细胞依靠外源丝氨酸消耗来维持嘌呤生物合成。为支持这一解释，提供外源性嘌呤核碱基，或增加 NAD ⁺可用性以促进从头丝氨酸和嘌呤合成，即使在没有细胞外丝氨酸的情况下也能挽救最大的增殖。总之，这些数据表明 NAD ⁺是癌细胞合成嘌呤生产所需的丝氨酸以支持快速增殖的内源性限制。