Locostatins identified as cancer drug targets
cell signalling pathways and cell migration, may suggest new
avenues for novel pharmaceutical therapies for treating a variety
of diseases, including cancer.
In identifying the protein, Raf Kinase Inhibitor Protein (RKIP), which controls kinase activity - a key component in the pathway responsible for determining cellular activity - scientists have the opportunity to target uncontrolled tumour growth.
However, RKIP's own activity is inhibited when a small molecule organic compound called locostatin, discovered earlier by University of Illinois at Chicago (UIC) researchers, binds to it.
"After finding that locostatin targets RKIP, we wanted to verify that RKIP really does control cell migration," said lead investigator Gabriel Fenteany, assistant professor of chemistry at UIC.
The researchers removed RKIP in the cell using a method called RNA interference and looked at the effect on cell migration.
They did the opposite manipulation as well - artificially increasing the amount of RKIP in the cell and again looking at the effect on cell migration.
In each case, the result was consistent with RKIP having an important, positive role in the control of cell migration.
"The interest in RKIP now is that it is a new and apparently important modulator of cell migration and therefore a possible target in anti-cancer strategies focused on limiting tumour angiogenesis and metastasis," Fenteany commented.
The findings are reported in the Sept. 26 issue of the journal Chemistry and Biology. Here they detail the approach of the research team, which is sometimes called "forward chemical genetics."
They first identified locostatin as an inhibitor of cell migration, then used locostatin itself as a kind of bait to fish out the protein to which it binds. That protein was RKIP.
"We have implicated this protein in controlling cell migration, a role it was not previously known to play," said Fenteany.
"It's a molecular target of locostatin. We found this on the basis of the chemical affinity of locostatin for this protein."
As a regulatory protein, RKIP controls the functions of kinases, thereby governing signalling pathways. When these pathways are not properly controlled, all kinds of diseases can result, including cancer.
More investigation on how exactly RKIP controls cell migration is needed said Fenteany.
UIC researchers are also trying to determine the potential of locostatin as a drug by looking at its effects on different types of cells and tissues.
