Metabolic reprogramming of metastatic breast cancer and melanoma bylet-7amicroRNA

// Anastassia Serguienko 1,2 , Iwona Grad 1,2 , Anna B. Wennerstrøm 1,2 , Leonardo A. Meza-Zepeda 1,3 , Bernd Thiede 4,5 , Eva W. Stratford 1,2 , Ola Myklebost 1,2,5 and Else Munthe 1,2 1 Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 2 Cancer Stem Cell Innovation Centre, Oslo, Norway 3 Genomics Core Facility, Oslo University Hospital, Oslo, Norway 4 The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway 5 Department of Biosciences, University of Oslo, Oslo, Norway Correspondence: Else Munthe, email: // Keywords : ROS, OXPHOS, glycolysis, mitochondria, HMOX1 Received : September 17, 2014 Accepted : December 10, 2014 Published : December 29, 2014 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.