MYC, Metabolism, Cell Growth, and Tumorigenesis
01 Aug 2013-Cold Spring Harbor Perspectives in Medicine (Cold Spring Harbor Laboratory Press)-Vol. 3, Iss: 8
TL;DR: Key genes involved in ribosomal and mitochondrial biogenesis, glucose and glutamine metabolism, lipid synthesis, and cell-cycle progression are robustly activated by MYC, contributing to the acquisition of bioenergetics substrates for the cancer cell to grow and proliferate.
Abstract: The MYC proto-oncogene is frequently activated in human cancers through a variety of mechanisms. Its deregulated expression, unconstrained by inactivation of key checkpoints, such as p53, contributes to tumorigenesis. Unlike its normal counterpart, which is restrained by negative regulators, the unleashed MYC oncogene produces a transcription factor that alters global gene expression through transcriptional regulation, resulting in tumorigenesis. Key genes involved in ribosomal and mitochondrial biogenesis, glucose and glutamine metabolism, lipid synthesis, and cell-cycle progression are robustly activated by MYC, contributing to the acquisition of bioenergetics substrates for the cancer cell to grow and proliferate.
Citations
More filters
TL;DR: Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials.
Abstract: Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.
787 citations
TL;DR: Tumors appear to be "addicted" to MYC because of both tumor cell-intrinsic, cell-autonomous and host-dependent, immune cell-dependent mechanisms.
Abstract: The MYC proto-oncogene has been implicated in the pathogenesis of most types of human tumors. MYC activation alone in many normal cells is restrained from causing tumorigenesis through multiple genetic and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis, and cellular senescence. When pathologically activated in a permissive epigenetic and/or genetic context, MYC bypasses these mechanisms, enforcing many of the "hallmark" features of cancer, including relentless tumor growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis, and altered cellular metabolism. MYC mandates tumor cell fate, by inducing stemness and blocking cellular senescence and differentiation. Additionally, MYC orchestrates changes in the tumor microenvironment, including the activation of angiogenesis and suppression of the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can result in the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumor regression, associated with tumor cells undergoing proliferative arrest, differentiation, senescence, and apoptosis, as well as remodeling of the tumor microenvironment, recruitment of an immune response, and shutdown of angiogenesis. Hence, tumors appear to be "addicted" to MYC because of both tumor cell-intrinsic, cell-autonomous and host-dependent, immune cell-dependent mechanisms. Both the trajectory and persistence of many human cancers require sustained MYC activation. Multiscale mathematical modeling may be useful to predict when tumors will be addicted to MYC. MYC is a hallmark molecular feature of both the initiation and maintenance of tumorigenesis.
614 citations
Cites background from "MYC, Metabolism, Cell Growth, and T..."
...These changes may make tumors particularly susceptible to the inhibition of enzymes that are essential for energy metabolism (Dang 1999, 2013; Dang et al. 2009; O’Shea and Ayer 2013)....
[...]
...The suppression of MYC may induce tumor regression by acutely disrupting the ability of tumor cells to maintain sufficient metabolism to sustain survival and/or by directly regulating death signaling (see Dang 2013; O’Shea and Ayer 2013; Morrish and Hockenbery 2014)....
[...]
TL;DR: An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells.
Abstract: Cancer is driven by genetic and epigenetic alterations that allow cells to overproliferate and escape mechanisms that normally control their survival and migration. Many of these alterations map to signaling pathways that control cell growth and division, cell death, cell fate, and cell motility, and can be placed in the context of distortions of wider signaling networks that fuel cancer progression, such as changes in the tumor microenvironment, angiogenesis, and inflammation. Mutations that convert cellular proto-oncogenes to oncogenes can cause hyperactivation of these signaling pathways, whereas inactivation of tumor suppressors eliminates critical negative regulators of signaling. An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells.
597 citations
TL;DR: An algorithm that determines the probability that a patient's lymphoma belongs to one of seven genetic subtypes based on its genetic features is described, suggesting a shared pathogenesis of DLBCL.
463 citations
Cites background from "MYC, Metabolism, Cell Growth, and T..."
...MYC induces ribosome biogenesis (Dang, 2013) and, accordingly, EZB-MYC tumors highly expressed a ribosomal protein signature....
[...]
...MYC induces ribosome biogenesis (Dang, 2013) and, accordingly, EZB-MYC+ tumors highly expressed a ribosomal protein signature....
[...]
TL;DR: In this paper, the authors examine the current understanding of axon regeneration mechanisms at cellular and molecular terms and discuss their potential implications for promoting axon recovery and functional recovery after nerve injury.
409 citations
References
More filters
01 Apr 2012
TL;DR: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis as mentioned in this paper, and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration.
Abstract: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.
6,268 citations
TL;DR: Recent advances in understanding of the mTOR pathway are reviewed and pharmacological approaches to treat human pathologies linked to mTOR deregulation are discussed.
5,792 citations
TL;DR: A hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production is revealed.
3,193 citations
"MYC, Metabolism, Cell Growth, and T..." refers background in this paper
...PDH is potently regulated by pyruvate dehydrogenase kinases (PDKs), which phosphorylate and inhibit PDH activity, particularly under hypoxia (Kim et al. 2006; Papandreou et al. 2006)....
[...]
TL;DR: It is demonstrated that deregulated c-myc expression induces apoptosis in cells growth arrested by a variety of means and at various points in the cell cycle.
3,047 citations
"MYC, Metabolism, Cell Growth, and T..." refers background in this paper
...In this regard, deregulated MYC expression predisposes cells to growth factor or nutrient deprivation-induced cell death, while deprived normal cells withdraw into the cell-cycle G1 phase (Askew et al. 1991; Evan et al. 1992; Shim et al. 1998; Yuneva et al. 2007)....
[...]
01 Jan 2005
TL;DR: In this article, the proto-oncogene c-myc was found to activate expression of a cluster of six miRNAs on human chromosome 13 and showed that miR-17-5p and miR20a are negatively regulated by E2F1.
Abstract: MicroRNAs (miRNAs) are 21–23 nucleotide RNA molecules that regulate the stability or translational efficiency of target messenger RNAs. miRNAs have diverse functions, including the regulation of cellular differentiation, proliferation and apoptosis. Although strict tissue- and developmental-stage-specific expression is critical for appropriate miRNA function, mammalian transcription factors that regulate miRNAs have not yet been identified. The proto-oncogene c-MYC encodes a transcription factor that regulates cell proliferation, growth and apoptosis. Dysregulated expression or function of c-Myc is one of the most common abnormalities in human malignancy. Here we show that c-Myc activates expression of a cluster of six miRNAs on human chromosome 13. Chromatin immunoprecipation experiments show that c-Myc binds directly to this locus. The transcription factor E2F1 is an additional target of c-Myc that promotes cell cycle progression. We find that expression of E2F1 is negatively regulated by two miRNAs in this cluster, miR-17-5p and miR-20a. These findings expand the known classes of transcripts within the c-Myc target gene network, and reveal a mechanism through which c-Myc simultaneously activates E2F1 transcription and limits its translation, allowing a tightly controlled proliferative signal.
2,752 citations