Metabolic reprogramming of metastatic breast cancer and melanoma by Let-7a microRNA
| Autor: | Anastassia Serguienko, Ola Myklebost, Leonardo A. Meza-Zepeda, Else Munthe, Eva W. Stratford, Iwona Grad, Anna B. Wennerström, Bernd Thiede |
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| Předmět: |
Mitochondrial ROS
Blotting Western Apoptosis Breast Neoplasms Mitochondrion Biology Oxidative Phosphorylation Breast cancer HMOX1 Cell Line Tumor microRNA medicine Humans Neoplasm Metastasis Melanoma Cell Proliferation Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling Cancer ROS glycolysis medicine.disease Cellular Reprogramming Metastatic breast cancer OXPHOS Enzymes Mitochondria Gene Expression Regulation Neoplastic MicroRNAs Oxidative Stress Oncology Doxorubicin Cancer cell Cancer research Energy Metabolism Reactive Oxygen Species Reprogramming Research Paper |
| Zdroj: | Scopus-Elsevier Oncotarget |
| Popis: | Let-7 microRNAs (miRNAs) are highly conserved well-established promoters of terminal differentiation that are expressed in healthy adult tissues and frequently repressed in cancer cells. The tumor suppressive role of let-7 in a variety of cancers in vitro and in vivo has been widely documented and prompted these miRNAs to be candidate genes for miRNA replacement therapy. In this study we described a new role of let-7a in reprogramming cancer metabolism, recently identified as a new hallmark of cancer. We show that let-7a down-regulates key anabolic enzymes and increases both oxidative phosphorylation and glycolysis in triple-negative breast cancer and metastatic melanoma cell lines. Strikingly, the accelerated glycolysis coexists with drastically reduced cancer features. Moreover, let-7a causes mitochondrial ROS production concomitant with the up-regulation of oxidative stress responsive genes. To exploit these increased ROS levels for therapeutic purposes, we combined let-7a transfection with the chemotherapeutic drug doxorubicin. In both cancer types let-7a increased cell sensitivity to doxorubicin. Pre-treatment with N-acetyl cysteine (NAC) totally abolished this effect, indicating that the increased doxorubicin sensitivity of let-7a cells depends on the redox pathway. We thus have demonstrated that let-7a plays a prominent role in regulating energy metabolism in cancer cells, further expanding its therapeutic potential. |
| Databáze: | OpenAIRE |
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