New regulators of apoptosis and chemoresistance identified

Using targeted RNA interference, or RNAi libraries, researchers at Harvard Medical School describe the first large-scale classification of kinase and phosphatase gene families on the basis of their role in apoptosis and cell survival. This study appears in the June issue of Nature Cell Biology.

Jeffrey MacKeigan, former HMS research fellow in cell biology now working at Novartis Institutes for Biomedical Research, and colleagues utilized RNAi to systematically screen the kinase and phosphatase component of the human genome. They found that 11 percent of kinases control cell survival. As expected, this research identified known survival kinases (such as SGK, AKT2, and PKC), members of the AGC family of kinases, and several novel regulators of apoptosis and chemoresistance.

“Interestingly, 32 percent of phosphatases and their regulatory subunits contribute to cell survival,” said MacKeigan, “revealing a previously unrecognized general role for phosphatases as negative regulators of apoptosis. This is important because phosphatases cannot be simply viewed as enzymes that oppose the action of kinases and can have a positive role in cell survival.”

The researchers also identified a group of phosphatases whose loss of function results in chemoresistance and implicates these phosphatases as potential tumor suppressors.

“Down regulation of many of these tumor suppressor phosphatases resulted in a marked cellular resistance to conventional chemotherapeutic agents. Therefore, finding out whether some of these phosphatases have inactivating mutations in specific cancers may help overcome drug resistance,” said MacKeigan.

Additionally, the study showed that down regulation of survival kinases using RNAi sensitizes resistant cells to low concentrations of chemotherapeutic agents, emphasizing that these kinases may be important drug targets. This highlights the potential future use of either RNAi or small molecule inhibitors to selectively sensitize tumor cells to cell death and therefore may result in less toxicity to normal cells.