Proteasomal System as a Target in Cancer Therapy
Betul Karademir
Department of Biochemistry, Medicine Faculty / Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, Istanbul, Turkey
Proteasomal degradation of oxidized proteins is a crucial mechanism to prevent the accumulation of cellular damage. The removal of the damage is generally a required process for healthy organisms to keep the integrity while in cancer cells the situation may be different. Cancer cells have higher proteasome activity compared to normal cells. During cancer treatment, cellular damage by chemotherapy is an expected process to be able to kill the tumor cells. And the accumulation of this damage accompanied by the decrease in protein repair and removal systems may increase the efficacy of the cancer therapy.
Proteasomal system has been focused since 1999 as a target of chemotherapy since it has crucial roles in the turnover of oxidatively damaged proteins and also many signaling proteins. Bortezomib is the first generation proteasome inhibitor which is being used in the treatment of many cancer types. Literally thousands of studies have been focused on bortezomib and its potential role of different pathways and clinical trials resulted in hopeful outcomes in patients. Besides bortezomib, other proteasome inhibitors have been developed as second generation drugs. These inhibitors were modified to increase the specificity and to decrease the neuropathic side effect of bortezomib.
In our laboratory, several cancer cell lines have been tested from different aspects of proteasomal activity. In addition to proteasome inhibitors, inhibition of heat shock proteins have been tested regarding the effect of heat shock proteins on proteasomal activity. Recently proteasome inhibitors bortezomib and carfilzomib have been tested on neural stem cells to investigate the mechanisms of peripheral neuropathy induced by these inhibitors.
Supported by TUBITAK COST-CM1001-110S281, TUBITAK 212T156 and TUBITAK 115Z137.
