Src inhibition enhances paclitaxel cytotoxicity in ovarian cancer cells by caspase-9-independent activation of caspase-3.
Src tyrosine kinase has been found to be overexpressed and activated in a high proportion of ovarian cancers and ovarian cancer cell lines. Furthermore, Src activation is associated with activation of growth and survival signaling pathways. The present study was conducted in order to determine the effects of Src inhibition on ovarian cancer cell survival in response to chemotherapeutic agents. Inhibition of Src, either pharmacologically or through expression of a Src dominant-negative fusion construct, enhanced the cytotoxicity of two different classes of chemotherapeutics: paclitaxel and cisplatinum, in both mouse and human ovarian cancer cells. Interestingly, Src inhibition also restored sensitivity to drug-resistant ovarian cancer cells. The increased cytotoxicity in response to Src inhibition was associated with a large increase in processing and activation of caspase-3. The activation of caspase-3 seems to be independent of cytochrome c release and caspase-9 activation. The present study indicates that Src tyrosine kinase may provide an important target for small molecule inhibition in ovarian cancer.
Chen
Ting
T
Department of Cell Biology, Vincent T. Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, 3900 Reservoir Road, Washington, D.C. 20007, USA.
Pengetnze
Yolande
Y
Taylor
Christopher C
CC
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000201:enzymology*; D017239:Paclitaxel / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C412373:AG 1879; D000972:Antineoplastic Agents, Phytogenic; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D045304:Cytochromes c; D019061:src-Family Kinases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D017239:Paclitaxel; D002945:Cisplatin