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AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth

Oncogene volume 23, pages 5853–5857 (2004)Cite this article

Abstract

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.

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Acknowledgements

This work was supported by National Cancer Institute Grants CA83638 (SPORE in Ovarian Cancer), CA77429, and CA06927, and by an appropriation from the Commonwealth of Pennsylvania. The following Fox Chase Cancer Center/Ovarian SPORE shared facilities were used in the course of this work: Cell Culture Facility, Flow Cytometry and Cell Sorting Facility, Biosample and Tissue Procurement Core, Biostatistics Facility and Histopathology Facility. HQ Wang is supported by a Board of Director's Postdoctoral Fellowship and by an NIH Institutional Training Grant.

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  1. Deborah A Altomare and Hui Qin Wang: These authors contributed equally to this work

Authors and Affiliations

  1. Human Genetics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, 19111, PA, USA

    Deborah A Altomare, Hui Qin Wang, Kristine L Skele, Assunta De Rienzo & Joseph R Testa

  2. Tumor Cell Biology, Fox Chase Cancer Center, Philadelphia, 19111, PA, USA

    Andres J Klein-Szanto

  3. Ovarian Cancer Programs, Fox Chase Cancer Center, Philadelphia, 19111, PA, USA

    Andrew K Godwin

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  1. Deborah A Altomare
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Correspondence to Joseph R Testa.

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Altomare, D., Wang, H., Skele, K. et al. AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene 23, 5853–5857 (2004). https://doi.org/10.1038/sj.onc.1207721

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