Rewiring Cell Metabolism Slows Cancer Growth

Many cancers have significantly less mitochondrial pyruvate
 carrier within them than normal adult cells. Mice were
 injected either with control colon cancer cells, or colon
 cancer cells in which mitochondrial pyruvate carrier had
 been re-introduced. The cancer cells with added MPC form
 tumors that are significantly smaller, at as little as one-fourth
the size. (Credit: Ralph DeBerardinis)
Cancer is an unwanted experiment in progress. As the disease advances, tumor cells accumulate mutations, eventually arriving at ones that give them the insidious power to grow uncontrollably and spread. Distinguishing drivers of cancer from benign mutations open opportunities for developing targeted cancer therapies.
 
A study reports that cancers select against a protein complex called the mitochondrial pyruvate carrier (MPC), and re-introduction of MPC in colon cancer cells impairs several properties of cancer, including growth. The research, which appears online in Molecular Cell, implicates changes in a key step in metabolism, the way cellular fuel is utilized, as an important driver of colon cancer that is also likely to be important in many other cancer settings.
 
Cancers appear to do whatever they can to get rid of MPC, a protein involved in carbohydrate metabolism, shows the study. At least 18 types of cancers – colon, brain, breast, and liver among them, have significantly less MPC than normal adult cells. Some cancers simply delete a region of the genome that contains one of the MPC genes, others find different ways to dampen MPC expression. In fact, a survey of patient biopsies shows that the less MPC there is, the more aggressive the cancer becomes.
 
Even more striking, when the researchers reintroduced MPC into colon cancer cell lines, properties that define them as cancerous, reverted. The cells divide less frequently under certain conditions and decrease expression of stem cell markers, an early step frequently defining the potential to form tumors and spread. Further, the engineered cells are dramatically impaired in their ability to form tumors after injection into mice. Tumors containing cells with MPC were as small as one-fourth the size of tumors made from cells without the protein complex.
 
The role of MPC in the normal cell, and what loss of MPC does to a cancer cell, addresses an observation first made nearly one century ago. Nobel Prize-wining biochemist Otto Warburg noted that cancer cells change their metabolism to support uncontrolled growth and proliferation. Scientists later found the way in which the metabolite pyruvate is processed is key to these metabolic changes. In normal adult cells, pyruvate enters the mitochondria, the cell's powerhouse, and fuels energy production. In cancer, pyruvate is diverted from the mitochondria to an alternative metabolic pathway that makes cell-building material.
 
Scientists had long suspected the so-called Warburg effect seen in cancer was contingent upon controlling entry of pyruvate into the mitochondria. But there was no way to directly test the idea until two years ago, when the researchers identified MPC as pyruvate's doorway to the mitochondria.
 
The current report in Molecular Cell shows that cancer cells shut that door by repressing MPC, and that experimentally re-opening the door by re-introducing MPC not only inhibits cancer growth, but also redirects pyruvate to the metabolic pathway used in normal cells. In other words, MPC counteracts the Warburg effect.
 
Understanding the Warburg effect has been an area of intense interest in recent years because of the potential to translate those discoveries into new cancer therapeutics. This information can be used to design therapies that are specifically toxic to cancer cells.