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Metabolic reprogramming of triple-negative breast cancer and melanoma cell lines by the Let-7a microRNA

ABSTRACT: Let-7 microRNAs (miRNAs) are a family of highly conserved well-established promoters of terminal differentiation that are expressed in all healthy adult tissues and frequently repressed in cancer cells. The tumour 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. Reprogrammed metabolism, recently identified as a new hallmark of cancer, contributes to cancer cell growth, proliferation, invasiveness and drug resistance. In this study we identified a new metabolic role of let-7a in triple-negative breast cancer and metastatic melanoma cell lines. We show that let-7a down-regulates key anabolic enzymes, promotes oxidative phosphorylation and mitochondrial ROS formation accompanied by the up-regulation of the oxidative stress responsive genes. To assess if we could exploit these increased ROS levels for therapeutic purposes, we combined let-7a transfection with the antitumor drug doxorubicin. In both cancer types we observed a stronger response to the doxorubicin treatment in let-7a transfected cells. Pre-treatment with an antioxidant N-acetyl cysteine totally abolished this difference, indicating that the increased doxorubicin sensitivity of let-7a cells depends on the redox pathway. We demonstrated that let-7a plays a prominent role in regulating energy metabolism in cancer cells. We propose that a benefit from let-7 miRNA replacement therapy could come not only from the repression of oncogenic pathways targeted directly by let-7, but also by increased sensitivity to chemotherapeutic agents through indirect metabolic changes caused by let-7. Investigation of let-7a metabolic role in breast cancer and melanoma cells.

SUBMITTER: Iwona Grad   Eva W Stratford  Anastassia Serguienko  Ola Myklebost  Else Munthe  Leonardo A. Meza-Zepeda  Leonardo A Meza-Zepeda  Anna B Wennerström  Bernd Thiede 

PROVIDER: E-GEOD-60326 | ArrayExpress | 2015-12-31



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