AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth.
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.
Altomare
Deborah A
DA
Human Genetics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Wang
Hui Qin
HQ
Skele
Kristine L
KL
De Rienzo
Assunta
A
Klein-Szanto
Andres J
AJ
Godwin
Andrew K
AK
Testa
Joseph R
JR
D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
D002867:Chromones; D002945:Cisplatin; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546842:MTOR protein, human; C494918:AKT1 protein, human