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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