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RanBP1 downregulation sensitizes cancer cells to taxol in a caspase-3-dependent manner

Oncogene volume 28, pages 1748–1758 (2009)Cite this article

Abstract

Mitotic microtubule (MT)-targeting drugs are widely used to treat cancer. The GTPase Ran regulates multiple processes, including mitotic spindle assembly, spindle pole formation and MT dynamics; Ran activity is therefore essential to formation of a functional mitotic apparatus. The RanBP1 protein, which binds Ran and regulates its interaction with effectors, is overexpressed in many cancer types. Several observations indicate that RanBP1 contributes to regulate the function of the mitotic apparatus: RanBP1 inactivation yields hyperstable MTs and induces apoptosis during mitosis, reminiscent of the effects of the MT-stabilizing drug taxol. Here we have investigated the influence of RanBP1 on spontaneous and taxol-induced apoptosis in transformed cells. We report that RanBP1 downregulation by RNA interference activates apoptosis in several transformed cell lines regardless of their p53 status, but not in the caspase-3-defective MCF-7 breast cancer cell line. Furthermore, RanBP1-interfered cells show an increased apoptotic response to taxol compared to their counterpart with normal or high RanBP1 levels, and this response is caspase-3 dependent. These results indicate that RanBP1 can modulate the outcome of MT-targeting therapeutic protocols.

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Acknowledgements

We thank Dr Christopher J Froelich (Northwestern University Medical School, Evanston, IL) for gifting the MCF-7/casp-3 cell line. We also thank Dr Giulia Guarguaglini for discussions and advice. This work was supported by the Italian Association for Cancer Research (AIRC) and by MIUR-FIRB (grant RBIN04T7MT). WMR and MC were supported by AIRC, ER and RM by MIUR-FIRB research contracts.

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  1. A Tedeschi

    Present address: 2Current address: Research Institute of Molecular Pathology, Dr Bohr-Gasse 7, A-1030 Vienna, Austria.,

  2. S A Di Gioia

    Present address: 3Current address: Department of Cellular Biotechnology and Hematology, Sapienza University of Rome, 00161 Rome, Italy.,

Authors and Affiliations

  1. IBPM Institute of Molecular Biology and Pathology, CNR National Research Council, c/o Sapienza University of Rome, Rome, Italy

    W M Rensen, E Roscioli, A Tedeschi, R Mangiacasale, M Ciciarello, S A Di Gioia & P Lavia

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Rensen, W., Roscioli, E., Tedeschi, A. et al. RanBP1 downregulation sensitizes cancer cells to taxol in a caspase-3-dependent manner. Oncogene 28, 1748–1758 (2009). https://doi.org/10.1038/onc.2009.24

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