Abstract
Metabolic reprogramming toward aerobic glycolysis and lactate fermentation supplies cancer cells with intermediate metabolites, which are used as macromolecule precursors. The oncogene MYC contributes to such aerobic metabolism by activating the expression of numerous genes essential for glycolysis and mitochondrial biogenesis. However, to survive and evolve in a hypoxic tumor milieu, cancer cells must revise MYC-driven metabolism because the mitochondrial respiratory chain provides free electrons to generate oxygen free radicals with inefficient production of ATP due to oxygen depletion. Instead, hypoxia-inducible transcription factor hypoxia-inducible factor 1 (HIF-1) takes over the role of MYC in glycolysis, but suppresses mitochondrial biogenesis and activity to protect cells from such threats. Recently, the N-MYC downstream-regulated gene (NDRG) family has received attention as potential biomarkers of cancer prognosis. NDRGs are repressed MYC-dependently in various cancers, but induced under hypoxia because HIF-1 directly activates their promoters and indirectly de-represses them by antagonizing MYC. In this review, we summarize the current understanding of the reprogramming of cancer metabolism via the counterbalance between MYC and HIF-1, and discuss the proven and putative roles of the NDRG family in adjusting cancer metabolism according to the ambient oxygen level.
Highlights
Cellular metabolism transition is a hallmark of cancer [1]
Cancer metabolism appears to be adapted to the anabolic program, which is under direct management by various oncogenes, such as MYC and hypoxia-inducible factor 1 (HIF-1) [8, 9]
This study focused on metastasis, we anticipate that LRP6 inhibition could underlie the effect of NDRG1 against Warburg metabolism
Summary
Cellular metabolism transition is a hallmark of cancer [1]. Positron-emission topography (PET), an imaging technique that uses the radiolabeled tracer 2-[18F]-fluoro-2-deoxy-D-glucose (FDG), enables visualization of glucose utilization in cancer patients and has shown that an increased rate of glycolysis is almost universally present in primary and metastatic tumors [2]. Cancer metabolism appears to be adapted to the anabolic program, which is under direct management by various oncogenes, such as MYC and hypoxia-inducible factor 1 (HIF-1) [8, 9]. HIF-1 reduces the overall mitochondrial mass by inducing BCL2/Adenovirus E1B 19 kDa interacting protein 3 (BNIP3), which triggers mitochondrial degradation through autophagy and halts the excessive production of mitochondrial ROS [18]. Such metabolic adjustments may reduce energy-consuming anabolic synthesis, and increase cell survival during hypoxia [11, 19].
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