State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China; Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
Cancer Lett. 2020 Mar 31;473:74-89. doi: 10.1016/j.canlet.2019.12.036. Epub 2020 Jan 2.
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.
胃肠道癌症由于治疗耐药性每年导致无数人死亡。然而，代谢改变是否导致化学耐药性尚不清楚。在这项研究中，我们报告在奥沙利铂处理的胃肠道癌细胞中激活了脂肪酸（FA）分解代谢，其限速酶肉碱棕榈酰基转移酶 1B（CPT1B）和 CPT2 的表达更高。临床分析还表明，这些酶的高表达与患者接受奥沙利铂为基础的化疗效果不佳有关。此外，用丙戊茶碱遗传或药理学抑制 CPT2 会破坏 NADPH 和氧化还原稳态，并增加氧化应激反应（ROS）生成和细胞凋亡在奥沙利铂处理后的胃肠道癌细胞中。具体而言，奥沙利铂和丙戊茶碱的联合显著抑制了基于细胞的异种移植和患者来源的异种移植（PDX）模型中胃肠道癌症的进展。从机制上讲，CPT2 被激活的 T 细胞核因子 3（NFATc3）转录上调，NFATc3 响应奥沙利铂处理而转位到细胞核中。总之，我们的研究表明，抑制 CPT 介导的 FA 分解代谢与传统化疗相结合是胃肠道癌症患者的一种有前途的治疗策略。
