Inhibition of fatty acid catabolism augments the efficacy of oxaliplatin-based chemotherapy in gastrointestinal cancers

Cancer Lett. 2020 Mar 31;473:74-89. doi: 10.1016/j.canlet.2019.12.036. Epub 2020 Jan 2.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Carcinogenesis / drug effects
  • Carcinogenesis / pathology
  • Carnitine O-Palmitoyltransferase / antagonists & inhibitors*
  • Carnitine O-Palmitoyltransferase / metabolism
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Drug Synergism
  • Fatty Acids / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • NADP / metabolism
  • NFATC Transcription Factors / metabolism
  • Oxaliplatin / pharmacology
  • Oxaliplatin / therapeutic use
  • Perhexiline / pharmacology
  • Perhexiline / therapeutic use
  • Reactive Oxygen Species
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / pathology
  • Up-Regulation / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Fatty Acids
  • NFATC Transcription Factors
  • NFATC3 protein, human
  • Reactive Oxygen Species
  • Oxaliplatin
  • NADP
  • CPT1B protein, human
  • Carnitine O-Palmitoyltransferase
  • Perhexiline