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Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis

Oncogene volume 23, pages 706–715 (2004)Cite this article

Abstract

Geranylgeranyltransferase I inhibitors (GGTIs) represent a new class of anticancer drugs. However, the mechanism by which GGTIs inhibit tumor cell growth is still unclear. Here, we demonstrate that GGTI-298 and GGTI-2166 induce apoptosis in both cisplatin-sensitive and -resistant human ovarian epithelial cancer cells by inhibition of PI3K/AKT and survivin pathways. Following GGTI-298 or GGTI-2166 treatment, kinase levels of PI3K and AKT were decreased and survivin expression was significantly reduced. Ectopic expression of constitutively active AKT2 and/or survivin significantly rescue human cancer cells from GGTI-298-induced apoptosis. Previous studies have shown that Akt mediates growth factor-induced survivin, whereas p53 inhibits survivin expression. However, constitutively active AKT2 failed to rescue the GGTIs downregulation of survivin. Further, GGTIs suppress survivin expression and induce programmed cell death in both wild-type p53 and p53-deficient ovarian cancer cell lines. These data indicate that GGTI-298 and GGTI-2166 induce apoptosis by targeting PI3K/AKT and survivin parallel pathways independent of p53. Owing to the fact that upregulation of Akt and survivin as well as inactivation of p53 are frequently associated with chemoresistance, GGTIs could be valuable agents to overcome antitumor drug resistance.

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Acknowledgements

We are grateful to Jian-dong Chen for GST-p53 plasmid and Benjamin K Tsang for ovarian cancer cell lines. We are also grateful to the Molecular Biology DNA Sequence Facility at H Lee Moffitt Cancer Center for sequencing Survivin constructs. This work was supported by National Cancer Institute Grants CA085709, CA67771, CA89242 and Department of Defense DAMD 17-01-1-0394 and DAMD17-02-1-0670.

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Authors and Affiliations

  1. Department of Pathology, University of South Florida College of Medicine, Tampa, 33612, FL, USA

    Han C Dan, Kun Jiang, Domenico Coppola, Santo V Nicosia & Jin Q Cheng

  2. Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, 33612, FL, USA

    Kun Jiang, Domenico Coppola, Santo V Nicosia, Said M Sebti & Jin Q Cheng

  3. Drug Discovery Program, University of South Florida College of Medicine, H Lee Moffitt Cancer Center, Tampa, 33612, FL, USA

    Kun Jiang, Said M Sebti & Jin Q Cheng

  4. Department of Chemistry, Yale University, New Haven, 06511, CT, USA

    Andrew Hamilton

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  1. Han C Dan
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  2. Kun Jiang
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  3. Domenico Coppola
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Correspondence to Said M Sebti or Jin Q Cheng.

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Dan, H., Jiang, K., Coppola, D. et al. Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis. Oncogene 23, 706–715 (2004). https://doi.org/10.1038/sj.onc.1207171

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