Tumor Cell Metabolism Depends on Both the Responsible Oncogene and Tissue Type

The metabolome represents the collection of all metabolites in a biological cell, tissue, organ, or organism, which are the end products of cellular processes.

Mutations in two proto-oncogenes have been linked to the development of several types of cancer. MYC (MYC v-myc myelocytomatosis viral oncogene homolog protein) is a transcription factor that activates expression of a great number of genes through binding on consensus sequences and recruiting histone acetyltransferases (HATs). By acting as a transcriptional repressor, MYC has a direct role in the control of DNA replication.

The MYC protein is a multifunctional, nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis, and cellular transformation. It functions as a transcription factor that regulates transcription of specific target genes. Mutations, overexpression, rearrangement, and translocation of this gene have been associated with a variety of hematopoietic tumors, leukemias, and lymphomas, including Burkitt lymphoma. MYC overexpression stimulates gene amplification, presumably through DNA over-replication.

The second proto-oncogene is c-MET, which encodes a protein known as hepatocyte growth factor receptor (HGFR). The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity. Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels that supply the tumor with nutrients, and cancer spread to other organs. MET is deregulated in many types of human malignancies, including cancers of kidney, liver, stomach, breast, and brain. Normally, only stem cells and progenitor cells express MET, which allows these cells to grow invasively in order to generate new tissues in an embryo or regenerate damaged tissues in an adult. However, cancer stem cells are thought to hijack the ability of normal stem cells to express MET, and thus become the cause of cancer persistence and spread to other sites in the body.

In a paper published in the February 8, 2012, issue of the journal Cell Metabolism investigators at the University of California, San Francisco (USA) reported significance differences between the metabolisms of tumors initiated by MYC and those initiated by MET. Furthermore, there were differences in MYC-induced kidney tumors and MYC-induced liver tumors.

A major difference between MYC and MET-induced tumors was linked to how the cancer cells metabolized two major nutrients: glucose and glutamine. MYC-induced mouse liver tumors significantly increased both glucose and glutamine catabolism, whereas MET-induced liver tumors used glucose to produce glutamine. Increased glutamine catabolism in MYC-induced liver tumors was associated with decreased levels of glutamine synthetase (Glul) and the switch from Gls2 to Gls1 glutaminase. In contrast to liver tumors, MYC-induced lung tumors displayed increased expression of both Glul and Gls1 and accumulated glutamine. Inhibition of Gls1 killed cells that overexpressed MYC and catabolized glutamine.

“Cancer research is dominated now by genomics and the hope that genetic fingerprints will allow us to guide therapy,” said senior author Dr. J. Michael Bishop, professor of microbiology and immunology at the University of California, San Francisco. “The issue is whether that is sufficient. We argue that it is not because metabolic changes are complex and hard to predict. You may need to have the metabolome as well as the genome. We should not lose sight of the rather immediate therapeutic potential.”

Related Links:
University of California, San Francisco