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Oncotarget. 2015 Feb 10;6(4):2451-65.

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

Author information

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.

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.

PMID:
25669981
PMCID:
PMC4385863
DOI:
10.18632/oncotarget.3235
[Indexed for MEDLINE]
Free PMC Article

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