[Kamat2010]

Ubiquitin is an essential protein present abundantly within the body and is used for the normal functioning and degradation of other proteins within the cell by covalent modification. The ubiquitin acts along with the Proteasome complex, which is multicatalytic proteinase. The Ubiquitin-Proteasome complex plays a very important role in the turnover of the different cellular proteins, which are usually degraded or damaged in nature, by the Ubiquitin-Protease pathway (UPP). The UPP has no effect in general on other normal proteins and the proteins, which are to be degraded, are targeted by the protease system by conjugation with ubiquitin.

The Ubiquitin-Protease system is responsible for the regulation of the mitosis and other important steps in the regulation of the cell cycle by the degradation of the damaged and unnecessary proteins, thereby preventing the accumulation of the unnecessary proteins within the cell. Thus, ubiquitin-protease system plays an important role in the maintenance of cellular homeostasis within the body by regulating the different signalling pathways, antigen-rocognition, etc. The accumulated damaged proteins within the cell cause apoptosis i.e. programmed cell death. This apoptosis is prevented by the Ubiquitin-protease system. Hence, the study of this system was undertaken to see if the inhibition of this system has any effect in promoting apoptosis of tumor cells thereby helping in cancer therapy. This could target either inhibition of the ubiquitination of the proteins to be degraded or the inhibition of the proteasomes, both of which cause protein degradation inhibition resulting ultimately in apoptosis.

The large sub-cellular organelle, which is multi-subunit protein complex, is the site for the ATP-dependent Ubiquitin mediated protein degradation within the cell and is known as Proteasome. The Proteasome is also known as 26S proteasome and consists of two subunits: 20S subunit, which is the catalytic subunit and the 19S subunit, which is the regulatory subunit. The 19S subunit consists of ATPases, which hydrolyse ATP thereby causing change in the conformation of the 20S subunit that binds to the unfolded substrate. The isopeptidase in the 19S subunit causes the cleavage of the ubiquitin molecules, which are then available for the ubiquitination of the subsequent proteins ready for degradation. Many research studies have proved that many inhibitors are available for the inhibition of the proteasome complexes, which ultimately lead to apoptosis. Some studies have proved the effectiveness of proteasome inhibition on the treatment of the multiple myeloma. Unlike other cells, multiple myeloma is susceptible to the accumulation of the unwanted proteins like large number of immunoglobulin chains as they are derived from the antibody producing cells. Due to this accumulation, the inhibition of the proteasome with the use of inhibitors causes the programmed cell death or apoptosis of the multiple myeloma cells. The normal cells are not affected in this case with the use of the proteasome inhibitors as the normal cells do not accumulate unwanted proteins in large quantities due to less need for proteasomal action. Moreover, the normal cells have alternative methods of removal of the damaged proteins like autophagy, whereby the unnecessary, aggregated proteins are transported to the lysosomes for removal, which helps in the removal of these proteins. Thus, it can be seen that this method of autophagy prevents apoptosis in some tumor cells. Hence, the use of inhibitors of autophagy along with the proteasome inhibitors may help in the apoptosis of the tumor cells better.

In some cases like breast cancer therapy, indirect function of the ubiquitin-protease system is seen. It is seen that the use of certain compounds was found to increase the ubiquitin mediated degradation of proteins required for normal cell function thereby causing apoptosis. The use of camptothecins was found to increase the proteolytic degradation of the topoisomerases by the ubiquin-mediated mechanisms. In some other cases, the oestrogen receptors were degraded by the UPP in the postmenopausal patients suffering from breast cancer with the use of certain drugs.

In this way, it can be seen that the UPP plays an important role in the different areas of cancer therapy. Extensive research is going on in this field and the exact mechanism by which the inhibition or the overfunctioning of the protease system plays a role in the programmed cell death of the tumor or cancer cells is yet to be analysed.