Sponagel Jasmin, Devarakonda Siddhartha, Rubin Joshua B, Luo Jingqin, Ippolito Joseph E
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
iScience. 2022 Oct 12;25(11):105339. doi: 10.1016/j.isci.2022.105339. eCollection 2022 Nov 18.
Lung cancer is the leading cause of cancer-related death. Intriguingly, males with non-small cell lung cancer (NSCLC) have a higher mortality rate than females. Here, we investigated the role of serine metabolism as a predictive marker for sensitivity to the antifolate pemetrexed in male and female NSCLC cell lines. Using [C] glucose tracing in NSCLC cell lines, we found that a subset of male cells generated significantly more serine from glucose than female cells. Higher serine biosynthesis was further correlated with increased sensitivity to pemetrexed in male cells only. Concordant sex differences in metabolic gene expression were evident in NSCLC and pan-cancer transcriptome datasets, suggesting a potential mechanism with wide-reaching applicability. These data were further validated by integrating antifolate drug cytotoxicity and metabolic pathway transcriptome data from pan-cancer cell lines. Together, these findings highlight the importance of considering sex differences in cancer metabolism to improve treatment for all patients.
肺癌是癌症相关死亡的主要原因。有趣的是，非小细胞肺癌（NSCLC）男性患者的死亡率高于女性。在此，我们研究了丝氨酸代谢作为男性和女性NSCLC细胞系对抗叶酸培美曲塞敏感性预测标志物的作用。通过在NSCLC细胞系中进行[C]葡萄糖追踪，我们发现一部分雄性细胞从葡萄糖产生的丝氨酸明显多于雌性细胞。仅在雄性细胞中，较高的丝氨酸生物合成与对培美曲塞的敏感性增加相关。NSCLC和泛癌转录组数据集中明显存在代谢基因表达的性别差异，提示了一种具有广泛适用性的潜在机制。通过整合泛癌细胞系的抗叶酸药物细胞毒性和代谢途径转录组数据，进一步验证了这些数据。总之，这些发现突出了在癌症代谢中考虑性别差异以改善所有患者治疗的重要性。
