Despite recent treatment advances, non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related deaths worldwide, and therefore it necessitates the exploration of new therapy options. One commonly shared feature of malignant cells is their ability to hijack metabolic pathways to confer survival or proliferation. In this study, we highlight the importance of the polyol pathway (PP) in NSCLC metabolism. This pathway is solely responsible for metabolizing glucose to fructose based on the enzymatic activity of aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD). Via genetic and pharmacological manipulations, we reveal that PP activity is indispensable for NSCLC growth and survival in vitro and in murine xenograft models. Mechanistically, PP deficiency provokes multifactorial deficits, ranging from energetic breakdown and DNA damage, that ultimately trigger the induction of apoptosis. At the molecular level, this process is driven by pro-apoptotic JNK signaling and concomitant upregulation of the transcription factors c-Jun and ATF3. Moreover, we show that fructose, the PP end-product, as well as other non-glycolytic hexoses confer survival to cancer cells and resistance against chemotherapy via sustained NF-κB activity as well as an oxidative switch in metabolism. Given the detrimental consequence of PP gene targeting on growth and survival, we propose PP pathway interference as a viable therapeutic approach against NSCLC.

尽管最近的治疗取得了进展，但非小细胞肺癌 （NSCLC） 仍然是全球癌症相关死亡的主要原因之一，因此需要探索新的治疗方案。恶性细胞的一个共同特征是它们能够劫持代谢途径以赋予生存或增殖。在这项研究中，我们强调了多元醇途径 （PP） 在 NSCLC 代谢中的重要性。该途径仅负责根据醛糖还原酶 （AKR1B1） 和山梨醇脱氢酶 （SORD） 的酶活性将葡萄糖代谢为果糖。通过遗传和药理学操作，我们揭示了 PP 活性对于体外和小鼠异种移植模型中 NSCLC 的生长和存活是必不可少的。从机制上讲，PP 缺乏会引发多因素缺陷，包括能量分解和 DNA 损伤，最终触发细胞凋亡的诱导。在分子水平上，这个过程是由促凋亡的 JNK 信号转导和伴随的转录因子 c-Jun 和 ATF3 的上调驱动的。此外，我们表明，果糖（PP 终产物）以及其他非糖酵解己糖通过持续的 NF-κB 活性以及新陈代谢中的氧化转换赋予癌细胞存活和对化疗的抵抗力。鉴于 PP 基因靶向生长和生存的有害后果，我们建议将 PP 通路干扰作为针对 NSCLC 的可行治疗方法。