Dataset Information

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

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.

SUBMITTER: Serguienko A

PROVIDER: S-EPMC4385863 | biostudies-other | 2015 Feb

REPOSITORIES: biostudies-other

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

Serguienko Anastassia A Grad Iwona I Wennerstrøm Anna B AB Meza-Zepeda Leonardo A LA Thiede Bernd B Stratford Eva W EW Myklebost Ola O Munthe Else E

Oncotarget 20150201 4

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 c ...[more]

PMID: 25669981

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Project description:Background:The complex yet interrelated connections between cancer metabolism and oncogenic driver genes are relatively unexplored but have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. The goal of this study was to identify global metabolic profiles of breast tumors isolated from multiple transgenic mouse models and to identify unique metabolic signatures driven by these oncogenes. Methods:Using mass spectrometry (GC-MS, LC-MS/MS, and capillary zone electrophoresis (CZE)-MS platforms), we quantified and compared the levels of 374 metabolites in breast tissue from normal and transgenic mouse breast cancer models overexpressing a panel of oncogenes (PyMT, PyMT-DB, Wnt1, Neu, and C3-TAg). We also compared the mouse metabolomics data to published human metabolomics data already linked to clinical data. Results:Through analysis of our metabolomics data, we identified metabolic differences between normal and tumor breast tissues as well as metabolic differences unique to each initiating oncogene. We also quantified the metabolic profiles of the mammary fat pad versus mammary epithelium by CZE-MS/MS. However, the differences between the tissues did not account for the majority of the metabolic differences between the normal mammary gland and breast tumor tissues. Therefore, the differences between the cohorts were unlikely due to cellular heterogeneity. Of the mouse models used in this study, C3-TAg was the only cohort with a tumor metabolic signature composed of ten metabolites that had significant prognostic value in breast cancer patients. Gene expression analysis identified candidate genes that may contribute to the metabolic reprogramming. Conclusions:This study identifies oncogene-induced metabolic reprogramming within mouse breast tumors and compares the results to that of human breast tumors, providing a unique look at the relationship between and clinical value of oncogene initiation and metabolism during breast cancer.

Dataset Information

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

Publications

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

Similar Datasets

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