Inhibition of fatty acid catabolism augments the efficacy of oxaliplatin-based chemotherapy in gastrointestinal cancers
| Autor: | Jia-huan Lu, De Shen Wang, Zexian Liu, Huai-Qiang Ju, Yun-Xin Lu, Zhao-Lei Zeng, Ming-Ming He, Hong-En Yu, Qi Zhao, Yan-Xing Chen, Qi-Nian Wu, Zhan-Hong Chen, Yun Wang, Feng Wang, Ying-Nan Wang, Rui-Hua Xu, Jia Liu, Hui Sheng |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinogenesis Colorectal cancer medicine.medical_treatment Perhexiline Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Stomach Neoplasms Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Animals Humans Medicine Gastrointestinal cancer Chemotherapy Carnitine O-Palmitoyltransferase NFATC Transcription Factors business.industry Catabolism Fatty Acids Drug Synergism medicine.disease Xenograft Model Antitumor Assays Up-Regulation Oxaliplatin Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Apoptosis 030220 oncology & carcinogenesis Cancer research Female Colorectal Neoplasms Reactive Oxygen Species business NADP medicine.drug |
| Zdroj: | Cancer Letters. 473:74-89 |
| ISSN: | 0304-3835 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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