Inhibition of fatty acid catabolism augments the efficacy of oxaliplatin-based chemotherapy in gastrointestinal cancers
Inhibition of fatty acid catabolism augments the efficacy of oxaliplatin-based chemotherapy in gastrointestinal cancers
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DOI：
10.1016/j.canlet.2019.12.036
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发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Ju, Huai-Qiang
中科院分区：
文献类型：
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作者：
Wang, Yun;Lu, Jia-Huan;Ju, Huai-Qiang
胃肠道癌每年因治疗耐药性导致无数人死亡。然而，代谢改变是否有助于化疗耐药性还不清楚。在这项研究中，我们报告，脂肪酸（FA）催化剂被激活的胃肠道癌细胞奥沙利铂治疗，表现出更高的表达限速酶肉毒碱棕榈酰转移酶1B（CPT 1B）和CPT 2。临床分析还表明，这些酶的高表达与患者中基于奥沙利铂的化疗结果较差相关。此外，在奥沙利铂治疗后，在胃肠道癌细胞中，用哌己西林对CPT 2的遗传或药理学抑制扰乱了NADPH和氧化还原稳态，并增加了活性氧（ROS）的产生和细胞凋亡。具体而言，奥沙利铂和哌克西林联合用药可显著抑制基于细胞的异种移植物和患者来源的异种移植物（PDX）模型中胃肠道癌的进展。从机制上讲，CPT 2被活化T细胞核因子3（NFATc 3）转录上调，后者在奥沙利铂治疗后易位至细胞核。总之，我们的研究表明，抑制CPT介导的FA catalysts联合常规化疗是一种有前途的治疗胃肠道肿瘤患者的策略。
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.