ReviewMYC and metabolism on the path to cancer
Introduction
MYC was first discovered as a cellular homolog of v-myc, a retroviral gene that was found to induce tumorigenesis in birds [1], [2]. Its role in human cancer was first recognized through observations of the pathognomonic chromosomal translocations, which juxtaposed the MYC gene next to constitutively active immunoglobulin enhancers, in human Burkitt's lymphoma [3], [4].
The MYC proto-oncogene is aberrantly overexpressed in over half of human cancers [5]. It is one of the most frequently amplified oncogene in human cancers and a member of the larger MYC family, which includes MYCN and MYCL [6], [7]. Dysregulations of MYC, such as amplification, chromosome translocation or loss of upstream repressors, have been found in many human cancers [8], [9].
MYC encodes the Myc transcription factor, which dimerizes with Max – another helix–loop–helix leucine zipper protein – to bind DNA and alter gene expression. Myc belongs to the extended Myc transcriptional factor network that includes Max, Mxd proteins, Mga, Mnt, Mxl, Mxlip, and the carbohydrate response element binding protein (ChREBP) [10]. Myc, as a transcriptional factor, activates many genes that are involved in cellular processes, including transcription, translation, chromatin modification and protein degradation.
Cancer cells take advantage of Myc's broad reach to reprogram and augment the most critical processes for survival, particularly metabolism. Metabolism is comprised of networks of pathways that can be categorized into distinct biological functions: catabolism, anabolism, and redox homeostasis. Catabolism involves multiple processes that break down nutrients to generate ATPs and produce reductive power as NADPH, whereas anabolism import and transform nutrients for macromolecule biosynthesis pathways to support cell growth and proliferation. These metabolic pathways involve the mitochondrion and oxidative phosphorylation that generates the bulk of reactive oxygen species (ROS). ROS can serve as signaling molecules, but at very high levels ROS can be toxic and must be titrated by redox homeostatic pathways. The balance between catabolism and anabolism is largely determined by external nutrients availability and cell states. While resting cells can equilibrate their bioenergetic demands with their environment, rapidly growing cancer cells often have a biomass demand that outstrips sources and confront limited nutrients and oxygen in the tumor microenvironment. By enhancing both catabolism and anabolism, Myc allows cancer cells to meet these challenges and sustain growth and proliferation.
In this review, we provide an overview of how Myc regulates cellular metabolism to promote growth and cooperates with other major metabolic drivers, thus providing for the reader a comprehensive view of metabolic control in growing cancer cells.
Section snippets
Cellular homeostasis
The activation of metabolic pathways is very dynamic and highly dependent on the state of cell and the external cues, such as growth signals and nutrients. Mammalian cells exhibit two major states in their life: resting state or dividing state. The majority of cells in our body are differentiated and in the resting state, using energy to maintain basal metabolism. In contrast, a small population of cells in our body exists in the dividing state, including intestinal mucosal cells and
Cell growth
Unlike resting cells, which strive to maintain homeostasis, rapid dividing cells undergo cell mass accumulation to promote growth and proliferation. Cell growth requires ATP, NADPH and a significant pool of building blocks, including fatty acids and cholesterol for cell membranes, nucleotides for DNA and RNA, amino acids for enzymes and structural proteins, and carbohydrates for post-translational modifications.
The fundamentals of cell growth have been extensively studied in simple organism
Transcription factor Myc
Myc is downstream of a number of growth-promoting signaling pathways, including those initiated by growth factor-stimulated receptor tyrosine kinases, T cell receptors and WNT signaling [5]. In non-transformed cells, cell cycle checkpoints protect against aberrant Myc activity. For example, p53-dependent apoptosis is induced upon acute Myc overexpression in primary mouse embryo fibroblasts [36]. Myc also induces expression of ARF, which directly inhibits Myc-mediated transcription and
Myc regulation of glucose and glutamine metabolism
As discussed earlier, yeast cells sense glucose and glutamine in the environment and activate expression of Ribi genes to initiate ribosome biogenesis [25]. In Drosophila, glucose activates insulin signaling, which acts through PI3K/Akt pathway to activate TOR and repress FOXO [47]. Drosophila Myc (dMyc) is identified as a convergent node downstream of TOR and FOXO signaling in response to nutrients [48]. When glucose is abundant, activated TOR rapidly increases dMyc protein to drive ribosome
Myc and the PI3K-Akt-mTOR pathway
Myc and the PI3K-Akt-mTOR pathway both respond to growth factor signaling and drive growth and metabolism in normal and neoplastic cells. While glycolysis is upregulated downstream of both, there are distinct metabolic programs associated with each oncoprotein. By studying dual-regulatable pre-B cell lines in which either Akt or Myc is overexpressed, it was observed that Myc drives both glycolysis and mitochondrial function, whereas Akt drives glycolysis alone [100]. Interestingly, these
Conclusion and future perspectives
Compelling evidence has underscored the multifaceted role of Myc in controlling cancer metabolism. Myc persistently emerges as a global growth regulator that drives glucose metabolism, glutamine metabolism, fatty acid synthesis, oxidative phosphorylation, nucleotide synthesis and ribosomal biogenesis (Fig. 5). Given the fact that Myc globally regulates multiple components of cellular processes, an outstanding question remains how Myc modulates pathways to ensure proper cellular function while
Acknowledgements
We thank Dr. Hong Kai Ji and Jason Ji for analyzing c-Myc-induced mouse liver model gene expression profiling (Fig. 1). The laboratory of C.V.D. is partially supported by the National Cancer Institute of the National Institutes of Health #R01CA057341, The Leukemia and Lymphoma Society #LLS 6106-14, and the Abramson Family Cancer Research Institute.
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