Abstract
ABSTRACTThe study of cellular metabolism has been rigorously revisited over the past decade, especially in the field of cancer research, revealing new insights that expand our understanding of malignancy. Among these insights is the discovery that various metabolic enzymes have surprising activities outside of their established metabolic roles, including in the regulation of gene expression, DNA damage repair, cell cycle progression and apoptosis. Many of these newly identified functions are activated in response to growth factor signaling, nutrient and oxygen availability, and external stress. As such, multifaceted enzymes directly link metabolism to gene transcription and diverse physiological and pathological processes to maintain cell homeostasis. In this Review, we summarize the current understanding of non-canonical functions of multifaceted metabolic enzymes in disease settings, especially cancer, and discuss specific circumstances in which they are employed. We also highlight the important role of subcellular localization in activating these novel functions. Understanding their non-canonical properties should enhance the development of new therapeutic strategies for cancer treatment.
Highlights
IntroductionWith the development of new experimental techniques, advances in cancer metabolism research have greatly enhanced our understanding of how cancer cells benefit from altered metabolism to support their growth
Altered metabolism has long been observed in cancer cells (Warburg, 1956a,b)
A growing list of multifaceted enzymes supports the possibility that cells employ existing proteins in different and efficient ways, without the need to replicate or transcribe additional genes. The aim of this Review is to provide an overview of metabolic enzymes for which non-canonical functions have been identified (Table 1) and to consider their implications in cancer
Summary
With the development of new experimental techniques, advances in cancer metabolism research have greatly enhanced our understanding of how cancer cells benefit from altered metabolism to support their growth. It is intriguing to speculate that these enzymes have unexpected nuclear functions, such as activating gene expression, which impacts specific cell decisions in response to fuel supply and demand. An emerging paradigm proposes that metabolic enzymes, rather than being components of biochemical pathways, are multi-functional proteins. They can act as mediators between growth stimuli, signaling pathways and downstream effectors, over and above the changes in metabolism, contributing to many other biological functions, such as gene transcription, apoptosis and cell cycle progression
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