The muscle-associated respiratory protein myoglobin (MB) is expressed in multiple types of cancer, including breast and prostate tumors. In Kaplan-Meier analyses of the two tumor types, MB positivity is associated with favorable prognoses. despite its well-characterized function in myocytes, the role of MB in cancer remains unclear. To study the impact of endogenous MB expression, small interfering RNA MB-knockdown cells were engineered using breast, prostate and colon cancer cell lines (MdA-MB468, LNcaP, dLd-1), and their transcriptomes were investigated using RNA-Seq at different oxygen levels. In MB-positive cells, increased expression of glycolytic genes was observed, which was possibly mediated by a higher activity of hypoxia-inducible factor 1α. In addition, the results of the gene set enrichment analysis suggested that MB contributed to fatty acid transport and turnover. MB-positive, wild-type-p53 LNcaP cells also exhibited increased expression of p53 target genes involved in cell cycle checkpoint control and prevention of cell migration. MB-positive cells expressing mutant p53 exhibited upregulation of genes associated with prolonged cancer cell viability and motility. Therefore, it was hypothesized that these transcriptomic differences may result from MB-mediated generation of nitric oxide or reactive oxygen species, thus employing established enzymatic activities of the globin. In summary, the transcriptome comparisons identified potential molecular functions of MB in carcinogenesis by highlighting the interaction of MB with key metabolic and regulatory processes.
Erythropoietin (EPO) improves neuronal mitochondrial function and cognition in adults after brain injury and in those afflicted by psychiatric disorders. However, the influence of EPO on mitochondria and cognition during development remains unexplored. We previously observed that EPO stimulates hippocampal-specific neuronal maturation and synaptogenesis early in postnatal development in mice. Here we show that EPO promotes mitochondrial respiration in developing postnatal hippocampus by increasing mitochondrial content and enhancing cellular respiratory potential. Ultrastructurally, mitochondria profiles and total vesicle content were greater in presynaptic axon terminals, suggesting that EPO enhances oxidative metabolism and synaptic transmission capabilities. Behavioural tests of hippocampus-dependent memory at early adulthood, showed that EPO improves spatial and short-term memory. Collectively, we identify a role for EPO in the murine postnatal hippocampus by promoting mitochondrial function throughout early postnatal development, which corresponds to enhanced cognition by early adulthood.
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