Response to energy depletion: miR-451/AMPK loop

The adaptation of cancer cells to the constantly changing conditions of their microenvironment during tumor progression requires dynamic and flexible mechanisms. Glioblastoma and other tumors cells require a continuous flux of nutrients and oxygen to sustain growth and elevated metabolism; yet, there is often insufficient supply of blood and energy to nourish this growth/metabolism. While the adaptive mechanisms to reduced oxygen (hypoxia) have been well defined, the adaptations to fluctuations in the major energy nutrient – i.e. glucose, are poorly comprehended. It is likely that the successful survival of a cancer cell depends on its ability to frequently and dynamically adjust for nutrient fluctuations. Reprogrammed glucose metabolism as a result of increased glycolysis and glucose uptake is a hallmark of numerous solid tumors and it was recently demonstrated that enhancing glucose uptake is one of the mechanisms of adaptation of glioblastoma cells to limited glucose availability [1]. The preferred uptake of glucose by cancer cells led us to hypothesize that in addition to an intracellular " sensor " pathway that monitors the fluctuations of environmental glucose; there must be the effector mechanisms that mediate adaptative response. It is known that cells exposed to low glucose become metabolically stressed. This results in a shortage of ATP, increasing the [AMP]/[ATP] ratio that activates the 5'AMP-activated protein kinase (AMPK) complex. AMPK is a highly conserved energy sensor belonging to a class of serine/threonine kinases that controls cell metabolism during environmental stress. When cellular energy levels are decreased (and thus the AMP/ATP ratio is increased), AMPK is phosphorylated by LKB1 [2]. Although the role of LKB1/AMPK axis in metabolic homeostasis is well documented, its function in cancer is much less clear. Our group has shown that the non-coding microRNA-miR-451, is a potent inhibitor of the AMPK signaling pathway [3] directly targeting CAB39-a necessary LKB1 co-activator. Glucose availability modulated the expression of miR-451 in glioblastoma cells. High glucose led to high levels of miR-451, shutting-off AMPK function, inhibiting cell migration and elevating cell proliferation. Conversely, low glucose led to AMPK activation, which diminished the levels of miR-451, inhibited cell growth and turned on a migratory phenotype [3]. These observations led us to postulate the existence of an AMPK/miR-451 reciprocal negative feedback loop, mediated by glucose availability. However, the molecular effectors facilitating the low glucose/active AMPK-mediated drop in miR-451 levels were not known. In our recent study, we showed that indeed the miR-451/AMPK loop is transcriptionally …