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Autotaxin delays apoptosis induced by carboplatin in ovarian cancer cells.

Susanne S Vidot, James J Witham, Roshan R Agarwal, Sebastian S Greenhough, Harnoor S HS Bamrah, Gabor J GJ Tigyi, Stanley B SB Kaye, and Alan A Richardson

Cell Signal 22(6):926-35 (2010) PMID 20100569

Drug resistance remains a barrier to the effective long term treatment of ovarian cancer. We have established an RNAi-based screen to identify genes which confer resistance to carboplatin or paclitaxel. To validate the screen we showed that siRNA interfering with the apoptosis regulators FLIP and Bcl-X(L) conferred sensitivity to paclitaxel and carboplatin respectively. The expression of 90 genes which have previously been shown to be over-expressed in drug-resistant ovarian cancer was inhibited using siRNA and the impact on sensitivity to carboplatin and paclitaxel was assessed. ENPP2 was identified as a candidate gene causing drug resistance. ENPP2 encodes autotaxin, a phospholipase involved in the synthesis of the survival factor lysophosphatidic acid. siRNA directed to ENPP2 resulted in earlier apoptosis following treatment with carboplatin. 2-carbacyclic phosphatidic acid (ccPA 16:1), a small molecule inhibitor of autotaxin, also accelerated apoptosis induced by carboplatin. Stable ectopic expression of autotaxin in OVCAR-3 cells led to a delay in apoptosis. When serum was withdrawn to remove exogenous LPA, ccPA caused a pronounced potentiation of apoptosis induced by carboplatin in cells expressing autotaxin. These results indicate that autotaxin delays apoptosis induced by carboplatin in ovarian cancer cells.

Copyright © 2010 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.cellsig.2010.01.017
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