Leucyl-trna Synthetase As A Potential Anti-cancer Target

Cancer is a deadly human disease that has multiple molecular causes and various types of cell origins. In addition, cancer cells often develop resistance to single-target anti-cancer drugs. Therefore, new anti-cancer targets are constantly called for in order to develop new chemotherapy drugs. We have found that some trypanosoma Leucyl-tRNA-synthetase (tbLeuRS) inhibitors also inhibited the growth of human cancer cells by the inhibition of human Leucyl-tRNA synthetase (hLeuRS/LARS). We propose that hLeuRS is a potential anti-cancer target and the inhibitors of this enzyme may develop into a new line of chemotherapy drugs. This thesis will try to verify this hypothesis through the design of a series of molecular, cellular and animal model experiments. The possible molecular mechanism of cancer cell inhibition by hLeuRS inhibitors is also touched on.This thesis shows that some compounds designed to inhibit tbLeuRS also inhibit hLeuRS in vitro, and hLeuRS inhibitors suppress tumor cell proliferation. The results also show hLeuRS inhibitor selectively inhibits cancer cells and this selectivity may reflect the preferred inhibition of fast growing cells, a common characteristic of cancer cells. Indeed, in a xenograft mouse model, hLeuRS inhibitor showed inhibition to tumor growth while had little sign of toxicity. Different from cyclohexmide, a general protein synthesis inhibitor, hLeuRS inhibitor activates p53 dependent p21 signaling pathway and promotes early apoptosis and G0/G1 cell cycle blocking.Taken together, this thesis proposed and showed hLeuRS is a potential anticancer drug target. These results will warrant the further study of hLeuRS as an anti-cancer target for the development of new lines of anti-cancer drugs.