title: Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA.
abstract: 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.
authors: Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Cancer Stem Cell Innovation Centre, Oslo, Norway.
authors: Anastassia
authors: A
authors: Serguienko
authors: Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Cancer Stem Cell Innovation Centre, Oslo, Norway.
authors: Iwona
authors: I
authors: Grad
authors: Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Cancer Stem Cell Innovation Centre, Oslo, Norway.
authors: Anna B
authors: AB
authors: Wennerstrøm
authors: Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Genomics Core Facility, Oslo University Hospital, Oslo, Norway.
authors: Leonardo A
authors: LA
authors: Meza-Zepeda
authors: The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway.|Department of Biosciences, University of Oslo, Oslo, Norway.
authors: Bernd
authors: B
authors: Thiede
authors: Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Cancer Stem Cell Innovation Centre, Oslo, Norway.
authors: Eva W
authors: EW
authors: Stratford
authors: Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Cancer Stem Cell Innovation Centre, Oslo, Norway.|Department of Biosciences, University of Oslo, Oslo, Norway.
authors: Ola
authors: O
authors: Myklebost
authors: Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Cancer Stem Cell Innovation Centre, Oslo, Norway.
authors: Else
authors: E
authors: Munthe
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D004734:Energy Metabolism / Q000235:genetics*; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004798:Enzymes; D035683:MicroRNAs; D017382:Reactive Oxygen Species; C487931:mirnlet7 microRNA, human; D004317:Doxorubicin