Abstract
SummaryCancer cells rely on mTORC1 activity to coordinate mitogenic signaling with nutrients availability for growth. Based on the metabolic function of E2F1, we hypothesize that glucose catabolism driven by E2F1 could participate on mTORC1 activation. Here, we demonstrate that glucose potentiates E2F1-induced mTORC1 activation by promoting mTORC1 translocation to lysosomes, a process that occurs independently of AMPK activation. We showed that E2F1 regulates glucose metabolism by increasing aerobic glycolysis and identified the PFKFB3 regulatory enzyme as an E2F1-regulated gene important for mTORC1 activation. Furthermore, PFKFB3 and PFK1 were found associated to lysosomes and we demonstrated that modulation of PFKFB3 activity, either by substrate accessibility or expression, regulates the translocation of mTORC1 to lysosomes by direct interaction with Rag B and subsequent mTORC1 activity. Our results support a model whereby a glycolytic metabolon containing phosphofructokinases transiently interacts with the lysosome acting as a sensor platform for glucose catabolism toward mTORC1 activity.
Highlights
Metabolic reprogramming is considered one of the hallmarks of cancer (Pavlova and Thompson, 2016)
We demonstrate that E2F1-dependent mTORC1 activation relies on glucose availability and identify the key regulatory enzymes, PFK/FBPase isoform 3 (PFKFB3) and PFK1, as proteins that interact with the lysosomal surface and regulate mTORC1 activity
Glucose Potentiates E2F1-Induced mTORC1 Activation by Promoting Its Translocation to Lysosomes As glucose is the main nutritional source for the maintenance of cancer cells growth, we investigated the importance of glucose for mTORC1 activation under E2F1 oncogenic signaling (Warburg, 1956)
Summary
Metabolic reprogramming is considered one of the hallmarks of cancer (Pavlova and Thompson, 2016). Cells must reach a critical size by promoting various anabolic processes required for growth, such as increased production of proteins, lipids, and nucleotides, and suppressing catabolic pathways like autophagy In this context, mTORC1 has emerged as a major metabolic reprogramming node that controls the balance between anabolism and catabolism in response to environmental cues. Given that several components within these pathways are oncogenes or tumor suppressors, deregulation of the TSC/Rheb axis is the main mechanism attributed to oncogenic transformation for controlling mTORC1 activity Despite this general agreement, some oncogenes use alternative pathways to regulate mTORC1 activity and cell growth such as E2F1 or c-Myc (Meo-Evoli et al, 2015; Pourdehnad et al, 2013)
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