AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth
Autor: | Kristine L Skele, Deborah A. Altomare, Joseph R. Testa, Hui Qin Wang, Assunta De Rienzo, Andres J. Klein-Szanto, Andrew K. Godwin |
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Rok vydání: | 2004 |
Předmět: |
Cancer Research
medicine.medical_specialty endocrine system diseases Morpholines Apoptosis Biology Protein Serine-Threonine Kinases medicine.disease_cause Ovarian tumor Phosphatidylinositol 3-Kinases Internal medicine Proto-Oncogene Proteins Genetics medicine Tumor Cells Cultured Humans Enzyme Inhibitors Phosphorylation Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Ovarian Neoplasms Sirolimus Cell growth TOR Serine-Threonine Kinases RPTOR medicine.disease Endocrinology Chromones Cancer research Female Cisplatin Ovarian cancer Carcinogenesis Protein Kinases Proto-Oncogene Proteins c-akt Cell Division medicine.drug |
Zdroj: | Oncogene. 23(34) |
ISSN: | 0950-9232 |
Popis: | Activation of the PI3K/AKT pathway may contribute to tumorigenesis. AKT mediates survival signals that protect cells from apoptosis and, thus, is a potentially important therapeutic target. To determine the frequency of AKT activation in human ovarian cancer, we screened a tumor tissue microarray with a phospho-specific pan-AKT (Ser473) antibody, which revealed elevated staining in 21 of 31 (68%) ovarian carcinomas. Phospho-AKT staining was associated with that of phospho (active)-mTOR in 27 of 31 (87%) ovarian tumors, with 17 (55%) tumors showing elevated phospho-mTOR positivity. We tested the effects of AKT/mTOR activation on the therapeutic sensitivity of ovarian cancer cells. Pretreatment of SKOV3 cells, which exhibit constitutive AKT activity under low serum conditions, with the PI3K inhibitor LY294002 augmented cisplatin-induced apoptosis. In contrast, ovarian cancer cell lines OVCAR4 and OVCAR5, which have low basal levels of AKT activity, did not show increased cisplatin-induced apoptosis when pretreated with LY294002. In addition, inhibition of mTOR activity with rapamycin resulted in G1 arrest in SKOV3 cells, but not in OVCAR4 or OVCAR5 cells. Collectively, these findings indicate that active AKT and downstream mTOR represent potentially important therapeutic and/or chemopreventive targets in ovarian cancer. |
Databáze: | OpenAIRE |
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