Autotaxin has been linked to chemoresistance through its
Autotaxin has been linked to chemoresistance through its ability to inhibit apoptosis induced by paclitaxel in breast cancer ABT-888  and LPA can inhibit cell death induced by cisplatin . Autotaxin was included in the present study because it was identified as being over-expressed in patients with recurrent disease after prior treatment with chemotherapy . It will be important to confirm these observations in a separate sample set although several studies (summarized in ) have reported gene copy number increases in ovarian cancer around chromosome region 8q24. This contains the gene encoding Myc, an oncogene implicated in ovarian cancer, as well as the gene encoding autotaxin, raising the possibility that the gene encoding autotaxin may be amplified in ovarian cancer. Indeed, autotaxin has been detected in ascites fluid from patients with ovarian cancer . We found that autotaxin significantly delays apoptosis induced by carboplatin. We have also observed that the Bcl-XL inhibitor ABT-737 also accelerates carboplatin-induced apoptosis  suggesting that delaying apoptosis may contribute to chemoresistance. This demonstrates the importance of investigating both short and long duration assays when screening and validating candidate drug-resistance genes. Firstly, what is the mechanism by which autotaxin delays apoptosis? Clearly, activation of survival pathways such as the Akt pathway by LPA and S1P are plausible mechanisms and we demonstrated that the ectopic expression of autotaxin activates Akt. However, autotaxin may also have a role in cell signaling that is independent of its catalytic phospholipase activity  and we have not yet been able to demonstrate a change in sensitivity to carboplatin following the addition of exogenous LPA or S1P. In breast cancer cells, lysophosphatidylcholine is required to allow autotaxin to prevent paclitaxel-induced cell death, supporting the notion that autotaxin may mediate chemoresistance through the generation of LPA . Additionally, the PI 3-kinase inhibitor Ly294004 inhibits paclitaxel-induced cell death . As PI 3-kinase and its downstream effector Akt are known to contribute to drug resistance , it is reasonable to suggest that autotaxin delays carboplatin-induced cell death through the generation of LPA and the subsequent activation of the PI 3-kinase/Akt pathway. Secondly, is autotaxin a suitable drug target? If the mechanism by which autotaxin delays cell death involves the synthesis of survival factors such as LPA or S1P, antagonists of the receptors for these survival factors may also be therapeutically useful. However, the receptors for these lipids comprise several subtypes and it is not yet clear which of these are the targets that it is appropriate to inhibit in order to increase sensitivity to chemotherapeutic agents. The inhibition of autotaxin offers the advantage of providing a single extracellular drug target that may block the production of LPA. However, S1P is also synthesized by sphingosine kinase and the inhibition of autotaxin may be inadequate to block the production of this lipid. This is not necessarily a barrier to the clinical use of autotaxin inhibitors because heterozygous ENPP2(+/−) mice have reduced autotaxin activity and reduced LPA levels, but levels of S1P are not affected. This suggests that the major physiological catalytic product of autotaxin is LPA  and the ability of autotaxin inhibitors to prevent the accumulation of LPA may be more significant than any effect on S1P. Bearing in mind that peritoneal fluid from patients with advanced ovarian cancer contains substantial quantities of LPA, treatment with an autotaxin inhibitor may be most appropriate following drainage of ascites fluid prior to chemotherapy to prevent the accumulation of LPA. Thirdly, is there sufficient reason to believe that inhibitors of autotaxin will be clinically efficacious? It appeared that the primary effect of autotaxin was to delay apoptosis induced by carboplatin, rather than have a significant effect upon the number of cells that survive following prolonged exposure to the drug, at least in the experimental settings used in this study. Thus, it is not clear whether an autotaxin inhibitor will be clinically useful. However, the exposure of tumor cells in a patient to carboplatin is transient, so accelerating the induction of apoptosis might be beneficial and may lead to greater cell kill. Currently, there are efforts to identify autotaxin inhibitors suitable for in vivo studies. Our results suggest that such inhibitors should be evaluated in ovarian cancer xenograft studies entailing a clinically-relevant exposure to carboplatin.