Abstract
Many transformed cells exhibit altered glucose metabolism and increased utilization of glutamine for anabolic and bioenergetic processes. These metabolic adaptations, which accompany tumorigenesis, are driven by oncogenic signals. Here we report that the transcription factor c-Jun, product of the proto-oncogene JUN, is a key regulator of mitochondrial glutaminase (GLS) levels. Activation of c-Jun downstream of oncogenic Rho GTPase signalling leads to elevated GLS gene expression and glutaminase activity. In human breast cancer cells, GLS protein levels and sensitivity to GLS inhibition correlate strongly with c-Jun levels. We show that c-Jun directly binds to the GLS promoter region, and is sufficient to increase gene expression. Furthermore, ectopic overexpression of c-Jun renders breast cancer cells dependent on GLS activity. These findings reveal a role for c-Jun as a driver of cancer cell metabolic reprogramming, and suggest that cancers overexpressing JUN may be especially sensitive to GLS-targeted therapies.
Highlights
Many transformed cells exhibit altered glucose metabolism and increased utilization of glutamine for anabolic and bioenergetic processes
To explore further the signalling connections that link Rho GTPases with GLS, we utilized an inducible, tetracycline-off, system to control the expression of oncogenicDbl in mouse embryonic fibroblasts (MEFs)
An important route for the delivery of glutamine-derived carbon into the tricarboxylic acid (TCA) cycle begins with the hydrolysis of glutamine to glutamate, a reaction catalysed by glutaminase
Summary
Many transformed cells exhibit altered glucose metabolism and increased utilization of glutamine for anabolic and bioenergetic processes. These metabolic adaptations, which accompany tumorigenesis, are driven by oncogenic signals. Increased nutrient uptake and re-routing of metabolites into anabolic processes are not passive adaptations to the proliferative state, but instead are tightly regulated by the signal transduction pathways and transcriptional networks that promote cell growth and cell cycle progression. Glutamine has many metabolic fates inside the cell, acting as a carbon and nitrogen source for biosynthetic reactions and contributing to redox homoeostasis[5,6,7] It is the role of glutamine as an anaplerotic substrate for the tricarboxylic acid (TCA) cycle that underlies the ‘glutamine addiction’ of many rapidly proliferating cells[10,11]. An apparent uncoupling of c-Myc and GLS has recently been described in human mammary epithelial cells as well as in certain breast cancer cell lines[26,27]
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