Oncotarget

Research Papers:

Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA

Anastassia Serguienko, Iwona Grad, Anna B. Wennerstrøm, Leonardo A. Meza-Zepeda, Bernd Thiede, Eva W. Stratford, Ola Myklebost and Else Munthe _

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Oncotarget. 2015; 6:2451-2465. https://doi.org/10.18632/oncotarget.3235

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Abstract

Anastassia Serguienko1,2, Iwona Grad1,2, Anna B. Wennerstrøm1,2, Leonardo A. Meza-Zepeda1,3, Bernd Thiede4,5, Eva W. Stratford1,2, Ola Myklebost1,2,5 and Else Munthe1,2

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.


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