AKT mediates the pro-survival effects of KIT in ovarian cancer cells and is a determinant of sensitivity to imatinib mesylate.
OBJECTIVE
Little is known about the function of KIT in ovarian cancer cells, despite its expression in most tumors and extensive speculation on the therapeutic value of its inhibition. This study investigated the consequences of KIT signaling on ovarian cancer cell proliferation and survival and evaluated the molecular basis of sensitivity to imatinib mesylate.


METHODS
Ovarian cancer cells were treated with KIT ligand (KL), the KIT neutralizing antibody ACK2, or imatinib mesylate and analyzed for changes in proliferation and chemosensitivity. Cells were analyzed for KIT, PDGF-R and AKT expression, which were then correlated with imatinib sensitivity. The importance of AKT in determining the sensitivity of cells to the drug was further evaluated by comparing the effects of, and co-treating with, imatinib and wortmannin.


RESULTS
Proliferation was unaffected by modulations to KIT signaling; however, pro-survival effects were observed. Specifically, KL increased and ACK2 decreased cisplatin resistance. Similarly, imatinib resulted in significant sensitization to cell death, albeit to varying degrees, in the five cell lines tested. All cell lines expressed at least one of the target molecules for imatinib, but responsiveness did not rely upon the expression of any one specific receptor. However, an inverse relationship between pAKT and imatinib sensitivity was identified. Decreasing pAKT with wortmannin did not achieve the equivalent cell killing as imatinib, but wortmannin did increase sensitivity to imatinib treatment.


CONCLUSIONS
This study demonstrates that KIT transduces anti-apoptotic signals and its inhibition with imatinib may represent a valuable therapeutic strategy for sensitizing chemoresistant ovarian cancer. pAKT may provide a mechanism of resistance to imatinib that correspondingly could serve as a predictor of sensitivity to treatment.
Shaw
Tanya J
TJ
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
Vanderhyden
Barbara C
BC
D000730:Androstadienes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D048708:Cell Growth Processes / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D051058:Oncogene Protein v-akt / Q000096:biosynthesis / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000096:biosynthesis / Q000494:pharmacology; D000077191:Wortmannin; D051636:X-Linked Inhibitor of Apoptosis Protein
D000730:Androstadienes; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D019089:Stem Cell Factor; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D051058:Oncogene Protein v-akt; D002945:Cisplatin; D000077191:Wortmannin