Suppression of oxidative phosphorylation and IDH2 sensitizes colorectal cancer to a naphthalimide derivative and mitoxantrone
| Autor: | Fujun Dai, Chaojie Wang, Yuxia Wang, Yuan Zhao, Songqiang Xie, Zhiyang Zhang, Lei Gao, Chaochao Ge, Kemeng Zhang, Yanming Wang, Yongli Feng, Xiaojuan Xu, Senzhen Wang |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death Citric Acid Cycle Down-Regulation Oxidative phosphorylation Mitochondrion medicine.disease_cause IDH2 Antioxidants Oxidative Phosphorylation Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Autophagy medicine Animals Humans chemistry.chemical_classification Mice Inbred BALB C Reactive oxygen species Cell Death HCT116 Cells Isocitrate Dehydrogenase Mitochondria Citric acid cycle Naphthalimides Oxidative Stress 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis Cancer research Mitoxantrone Colorectal Neoplasms Reactive Oxygen Species HT29 Cells Oxidative stress |
| Zdroj: | Cancer Letters. 519:30-45 |
| ISSN: | 0304-3835 |
| Popis: | Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Oxidative phosphorylation (OXPHOS) has attracted a considerable attention in CRC. It is of great interest to explore novel therapies that inhibit OXPHOS for CRC treatment. Compound 6c is a novel naphthalimide derivative. However, the effects of 6c on CRC and the underlying mechanism are unclear. In this study, 6c suppressed CRC tumor growth and metastasis. RNA-seq data showed that 6c triggered the inhibition of OXPHOS and tricarboxylic acid cycle. 6c specifically inhibited mitochondrial complex III activity and the expression of isocitrate dehydrogenase 2 (IDH2), resulting in oxidative stress. Antioxidants reversed 6c-induced cell death, senescence, and autophagosomes formation. 6c inhibited autophagy flux; however, pretreatment with autophagy inhibitors resulted in the reduction of 6c-induced cytoplasmic vacuolization and proliferation inhibition. Moreover, combinatory treatment of 6c and mitoxantrone (MIT) showed stronger inhibitory effects on CRC compared with the single agent. Downregulation of IDH2 induced reactive oxygen species production, leading to MIT accumulation and autophagic cell death after co-treatment with 6c and MIT. In summary, our findings indicated 6c as a promising candidate for CRC treatment. |
| Databáze: | OpenAIRE |
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