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Proteasome Regulation in Cancer
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The proteasome is a large complex found in eukaryotic cells, as well as archaea and some bacteria, which functions to break down and recycle old, damaged, or unnecessary proteins. Damaged proteins are targeted to the proteasome for degredation by binding of a protein called ubiquitin. Once the protein has been completely broken down, the amino acids can be recycled by the cell and used to make new proteins. Being able to break down proteins when they are no longer needed is an essential regulatory function that the cell uses. The proteasome is needed to control the cell cycle, gene expression, and prevent deleterious effects from improperly folded or over expressed proteins. Improper regulation of the proteasome has been linked with many diseases, from cancer to neurodegenerative diseases, demonstrating how important proper function of the proteasome is to the cell.

Over expression and over activation of the components of the proteasome has been associated with some diseases however. Multiple myeloma is a cancer of bone marrow cells. Excessive expression and activation of the proteasome has been noted in multiple myeloma cancer cells as well as many other cancers. Blockade of proteasome function has been shown to be harmful to these cancer cells in vitro as well as in clinical trials. Cancer results from an accumulation of various mutations to genes that help control the cell cycle. Some of these mutations may intensify proteins that increase replication in the cell, and some mutations may inactivate proteins that stop replication. Together, these mutations increase the rate of replication of the cell, which results in uncontrolled cell growth. When enough mutations accumulate, the cells become cancerous, and can cause damage to the host. The proteasome appears to be upregulated in cancer cells, with more proteasomes being assembled and activated. This may help the cancer cells remove all the excess, unnecessary proteins that develop when the cell cycle becomes disrupted.

Proteasome inhibitors have been studied in clinical trials for patients with cancer. One protein inhibitor, called Velcade, has been approved by the FDA for treatment of cancers including multiple myeloma. These proteasome inhibitors have been shown to selectively kill cancer cells and other rapidly replicating cells, while leaving normal cells relatively unharmed. While the proteasome inhibitor can be effective therapeutically, side effects include peripheral neuropathy , due to the effect of decreased proteasome function in normal cells. In addition, drug resistance to these proteasome inhibitors can pose a problem for patients that require multiple treatments or that have recurrent cancer. Drug resistance is a big problem for patients with incurable cancers such as multiple myeloma, where long term treatment is indicated.

Researchers have identified an enzyme, known as tankyrase, as a regulatory factor for the proteasome. Tankyrase is able to inhibit proteasome assembly. Tankyrase is upregulated when the cell is stressed, providing more active proteasomes to help degrade unnecessary and potentially harmful proteins and clean up the cell. In addition, researchers have discovered a small molecule, which is termed XAV939, can specifically block the function of tankyrase. By blocking tankyrase, the assembly of the proteasome would be inhibited. However, proteasomes that have already been assembled and are active would not be affected. This means that excessive proteasome activation, such as what has been demonstrated in multiple myeloma and other cancer cells, would be prevented. Researchers believe that normal proteasome function in healthy cells would not be as severely affected. In fact, they have shown in vitro that treatment of multiple myeloma cells with XAV939 does not affect the basal level of proteasomes in the cell. This would prevent the side effects seen during treatment with conventional proteasome inhibitors that completely block the function of the proteasome in all cell types.

In addition to potential cancer therapeutics, research regarding regulation of the proteasome could also be used as a treatment against muscle wasting and neurodegenerative disorders. Excessive activation of the proteasome in these disorders causes the cell to break down necessary proteins, leading to loss of muscle cells. Again, by inhibiting the proteasome through tankyrase inhibitors, scientists hope to prevent or reduce muscle loss in these patients. Indeed, understanding how the proteasome is regulated will have far reaching impacts in many areas of biology, biotechnology, and medical science.


References:

http://www.sciencedaily.com/releases/201...114644.htm
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