MYC, metabolism, cell growth, and tumorigenesis

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.

Figure 1.

Growth factor (doughnut) receptor engagement signals TOR activation through PI3K and MYC activation through the MEK-ERK pathway. MYC in turn stimulates genes involved in amino acid import and protein synthesis, particularly the aminoacyl-tRNA synthetases. The imported amino acids, such as leucine, further activate mTOR activity. The timing of events is only for heuristic purposes and is not based on evidence.

Figure 2.

MYC is depicted to induce genes involved in glycolysis and glutaminolysis. MYC induction of glucose and glutaminase transporters allow for import of these nutrients, which are depicted to be metabolized and enter the tricarboxylic acid (TCA) cycle (circle in the mitochondrion) to form hybrid intermediates with carbons derived from glucose and glutamine. Glucose is also shown converted to lactate, which is exported by a monocarboxylate transporter Mct1 that is potently activated by MYC. AKT is shown to also increase the glucose-transporting activity.

Figure 3.

MYC is shown to induce genes involved in nucleotide synthesis. Both glucose and glutamine provide the carbon skeleton and nitrogen for the de novo synthesis of pyrimidines and purines. Pools of nucleotides, NTPs and dNTPs, support nucleic acid synthesis for transcription and DNA replication.

Figure 4.

MYC is shown to stimulate genes involved in lipid synthesis. Citrate generated from glucose or glutamine is converted to acetyl-CoA for fatty acid synthesis. Glycerol coming from glucose provides the glyceride backbone for lipid synthesis. Not shown is the pathway for cholesterol synthesis, which is likely to be dependent on SREBP.

Figure 5.

MYC activates genes involved in mitochondrial and ribosomal biogenesis. The figure depicts the synthesis of rRNAs and ribosomal proteins, which are imported into the nucleolus for ribosome assembly. Assembled ribosomes are exported to support the synthesis of proteins for the growing cell. Mitochondria are duplicated along with mtDNA replication.