Gastrointestinal cancer causes countless deaths every year due to therapeutic resistance. However, whether metabolic alterations contribute to chemoresistance is not well understood. In this study, we report that fatty acid (FA) catabolism was activated in gastrointestinal cancer cells treated with oxaliplatin, which exhibited higher expression of the rate-limiting enzymes carnitine palmitoyltransferase 1B (CPT1B) and CPT2. The clinical analysis also showed that high expression of these enzymes was associated with poor oxaliplatin-based chemotherapy outcomes in patients. Furthermore, genetic or pharmacological inhibition of CPT2 with perhexiline disturbed NADPH and redox homeostasis and increased reactive oxygen species (ROS) generation and cell apoptosis in gastrointestinal cancer cells following oxaliplatin treatment. Specifically, the combination of oxaliplatin and perhexiline significantly suppressed the progression of gastrointestinal cancer in cell-based xenograft and patient-derived xenograft (PDX) models. Mechanistically, CPT2 was transcriptionally upregulated by nuclear factor of activated T cells 3 (NFATc3), which translocated to the nucleus in response to oxaliplatin treatment. In summary, our study suggests that the inhibition of CPT-mediated FA catabolism combined with conventional chemotherapy is a promising therapeutic strategy for patients with gastrointestinal cancers.

中文翻译：

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抑制脂肪酸分解代谢可增强基于奥沙利铂的化学疗法在胃肠道癌症中的功效。

胃肠道癌每年因治疗耐药性导致无数死亡。然而，尚不清楚代谢改变是否有助于化学抗性。在这项研究中，我们报告说，在用奥沙利铂治疗的胃肠道癌细胞中，脂肪酸（FA）分解代谢被激活，这显示出限速酶肉碱棕榈酰转移酶1B（CPT1B）和CPT2的更高表达。临床分析还表明，这些酶的高表达与患者基于奥沙利铂的化疗效果差有关。此外，用奥沙利铂治疗后胃肠道癌细胞对CPT2的遗传或药理抑制作用干扰了NADPH和氧化还原稳态，并增加了活性氧（ROS）的产生和细胞凋亡。特别，在基于细胞的异种移植物和患者衍生的异种移植物（PDX）模型中，奥沙利铂和perhexiline的组合可显着抑制胃肠道癌的进展。从机制上讲，CPT2在转录水平上被活化的T细胞3（NFATc3）的核因子上调，后者响应奥沙利铂治疗而易位至细胞核。总而言之，我们的研究表明，结合CPT介导的FA分解代谢的抑制作用与常规化学疗法相结合，对于胃肠道癌患者是一种有前途的治疗策略。响应奥沙利铂治疗而转移到细胞核。总而言之，我们的研究表明，结合CPT介导的FA分解代谢的抑制作用与常规化学疗法相结合，对于胃肠道癌患者是一种有前途的治疗策略。响应奥沙利铂治疗而转移到细胞核。总而言之，我们的研究表明，与常规化学疗法相结合的抑制CPT介导的FA分解代谢对于胃肠道癌患者是一种有前途的治疗策略。