Autotaxin delays apoptosis induced by carboplatin in ovarian cancer cells.
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 When serum was withdrawn to remove exogenous LPA, ccPA caused a pronounced potentiation of apoptosis induced by carboplatin in cells expressing autotaxin.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.
Vidot
Susanne
S
Section of Medicine, The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, United Kingdom.
Witham
James
J
Agarwal
Roshan
R
Greenhough
Sebastian
S
Bamrah
Harnoor S
HS
Tigyi
Gabor J
GJ
Kaye
Stanley B
SB
Richardson
Alan
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D043264:Phosphodiesterase I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D000099189:Lysophospholipase D
D000970:Antineoplastic Agents; D016190:Carboplatin; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D000099189:Lysophospholipase D