Search

The PPM1D gene is aberrantly amplified in a range of common cancers and encodes a protein phosphatase that is a potential therapeutic target. However, the issue of whether inhibition of PPM1D in human tumour cells that overexpress this protein compromises their viability has not yet been fully addressed. We show here, using an RNA interference (RNAi) approach, that inhibition of PPM1D can indeed reduce the viability of human tumour cells and that this effect is selective; tumour cell lines that overexpress PPM1D are sensitive to PPM1D inhibition whereas cell lines with normal levels are not. Loss of viability associated with PPM1D RNAi in human tumour cells occurs via the activation of the kinase P38. To identify chemical inhibitors of PPM1D, a high-throughput screening of a library of small molecules was performed. This strategy successfully identified a compound that selectively reduces viability of human tumour cell lines that overexpress PPM1D. As expected of a specific inhibitor, the toxicity to PPM1D overexpressing cell lines after inhibitor treatment is P38 dependent. These results further validate PPM1D as a therapeutic target and identify a proof-of-principle small molecule inhibitor.

Loss-of-function mutations in the LKB1 (STK11) serine-threonine kinase gene cause Peutz-Jeghers syndrome, which is associated with inherited susceptibility to colorectal and other cancers. No downstream targets of LKB1 kinase activity have been identified. Here we show that LKB1 can direct the phosphorylation of the serine-threonine kinase PAR1A. The amino-acid residues phosphorylated as a result of LKB1 activity have been identified and phosphorylation at these residues is required for PAR1A kinase activity. PAR1A has previously been implicated as a positive regulator of the Wnt-betacatenin signalling pathway. We show here that LKB1 can modify transcription driven by the Wnt-regulated TCF response element, implicating LKB1 in a pathway known to play a key role in human colorectal tumorigenesis.