Correction: A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D.

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.

Biochemical and cytogenetic biomarkers of pollutant exposure in marine fish (Aldrichetta forsteri Valenciennes and Sillago schomburgkii Peters) near industrial and metropolitan centres in South Australia.

This project aimed to measure biochemical and cytogenetic biomarkers in marine fish (Aldrichetta forsteri and Sillago schomburgkii) associated with industrial and urban centres in South Australia. These sites were Port Pirie (affected by metal-contaminated outflows), Barker Inlet (adjacent to Metropolitan Adelaide), and Wills Creek (reference site). The biochemical biomarkers included sorbitol dehydrogenase (SDH) and alanine aminotransferase (ALAT) in serum, adenylate levels (ATP, ADP and AMP) and adenylate energy charge (AEC) in gill and liver, and sodium/potassium ATPase (Na(+), K(+)-ATPase) in gill. Erythrocyte micronucleus frequency was a marker of cytogenetic effect. Serum enzyme levels were generally higher in fish from Port Pirie and Barker Inlet than in those from Wills Creek, with SDH demonstrating the clearest site-associated differences. Tissue adenylates were consistently lower at Port Pirie than elsewhere, suggesting a greater metabolic strain in fish at this site. AEC in gill and liver were consistently lower at Port Pirie than at Wills Creek, with Barker Inlet generally between these two. The reversed rank order was observed with erythrocyte micronucleus frequencies. Seasonal variations in the biomarkers may be attributed either to seasonal physiological changes in fish or changes in pollutant input levels or compositions. Na(+), K(+)-ATPase did not differ between sites nor seasons in this study. This work shows that biochemical and cytogenetic differences occur in marine fish at specific locations in South Australia. It also shows that of these tests, serum SDH and erythrocyte micronuclei are potentially the most sensitive and reliable biomarkers of pollutants effects on marine fish. The results also suggest that these data may be used as a baseline against which future changes in marine water quality, and their consequent biological effects, can be compared.