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.
Keywords: CPT; Chemoresistance; Colorectal cancer; FAO; Gastric cancer.
Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.
Conflict of interest statement
Declaration of competing interest All authors have no financial disclosures and no conflict of interest.
NKX2-8 deletion-induced reprogramming of fatty acid metabolism confers chemoresistance in epithelial ovarian cancer.EBioMedicine. 2019 May;43:238-252. doi: 10.1016/j.ebiom.2019.04.041. Epub 2019 Apr 29. EBioMedicine. 2019. PMID: 31047858 Free PMC article.
MALAT1 Is Associated with Poor Response to Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients and Promotes Chemoresistance through EZH2.Mol Cancer Ther. 2017 Apr;16(4):739-751. doi: 10.1158/1535-7163.MCT-16-0591. Epub 2017 Jan 9. Mol Cancer Ther. 2017. PMID: 28069878
Role of Reactive Oxygen Species in the Abrogation of Oxaliplatin Activity by Cetuximab in Colorectal Cancer.J Natl Cancer Inst. 2015 Dec 30;108(6):djv394. doi: 10.1093/jnci/djv394. Print 2016 Jun. J Natl Cancer Inst. 2015. PMID: 26719345 Free PMC article.
Oxaliplatin. A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies.Drugs. 2000 Oct;60(4):895-924. doi: 10.2165/00003495-200060040-00005. Drugs. 2000. PMID: 11085200 Review.
Oxaliplatin: a review of its use in combination therapy for advanced metastatic colorectal cancer.Drugs. 2003;63(19):2127-56. doi: 10.2165/00003495-200363190-00013. Drugs. 2003. PMID: 12962525 Review.