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Analysis of gene expression identifies PLAB as a mediator of the apoptotic activity of fenretinide in human ovarian cancer cells

Oncogene volume 26, pages 3952–3962 (2007)Cite this article

Abstract

Fenretinide (4-HPR) is a synthetic retinoid with antitumor activity, which induces apoptosis in cancer cell lines of different histotypes. To identify genes contributing to its apoptotic activity in ovarian cancer cells, we monitored, by cDNA arrays, gene expression changes after 4-HPR exposure in A2780, a human ovarian carcinoma cell line sensitive to the retinoid. Among the differentially expressed transcripts, PLAcental Bone morphogenetic protein (PLAB), a proapoptotic gene, was the most highly induced. In a panel of ovarian carcinoma cell lines with different 4-HPR sensitivities, PLAB upregulation was associated with cellular response to 4-HPR, its overexpression increased basal apoptosis and its silencing by small interfering RNA decreased the ability of 4-HPR to induce apoptosis. PLAB induction by 4-HPR was p53- and EGR-1 independent and was regulated, at least in part, by increased stability of PLAB mRNA. PLAB up-modulation by 4-HPR also occurred in vivo: in ascitic cells collected from patients with ovarian cancer before and after 4-HPR treatment, PLAB was upmodulated in 2/4 patients. Our results in certain ovarian cancer cell lines indicate a role for PLAB as a mediator of 4-HPR-induced apoptosis. The correlation of increased PLAB in vivo with antitumor activity remains to be established.

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Acknowledgements

We are grateful to Dr Perego for kindly giving us IGROV-1/Pt cells. The study was supported by grants from the Associazione Italiana per la Ricerca sul Cancro, Milan, Italy and the American Cancer Society Research Scholar grant RSG-04-170-01-CNE to JRL.

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Authors and Affiliations

  1. Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy

    V Appierto, M G Villani, E Cavadini, M Gariboldi, L De Cecco, M A Pierotti, J Reid, P Tiberio & F Formelli

  2. Molecular Cancer Genetics Group, Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy

    M Gariboldi, L De Cecco, M A Pierotti & J Reid

  3. Department of Pathology, University of Colorado at Denver and Health Sciences Center Aurora, CO, USA

    J R Lambert

  4. Division of Gynecologic Oncology, European Institute of Oncology, University of Milan Bicocca, Milan, Italy

    N Colombo

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  1. V Appierto
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Correspondence to F Formelli.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Appierto, V., Villani, M., Cavadini, E. et al. Analysis of gene expression identifies PLAB as a mediator of the apoptotic activity of fenretinide in human ovarian cancer cells. Oncogene 26, 3952–3962 (2007). https://doi.org/10.1038/sj.onc.1210171

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