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Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines

  • Authors:
    • Kana Miyahara
    • Hiromi Kazama
    • Hiroko Kokuba
    • Seiichiro Komatsu
    • Ayako Hirota
    • Jun Takemura
    • Kazuhiro Hirasawa
    • Shota Moriya
    • Akihisa Abe
    • Masaki Hiramoto
    • Takashi Ishikawa
    • Keisuke Miyazawa
  • View Affiliations / Copyright

    Affiliations: Department of Breast Surgery, Tokyo Medical University, Tokyo, Japan, Department of Biochemistry, Tokyo Medical University, Tokyo, Japan, Laboratory of Electron Microscopy, Tokyo Medical University, Tokyo, Japan, Department of Otolaryngology (Head and Neck Surgery), Tokyo Medical University, Tokyo, Japan
    Copyright: © Miyahara et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1848-1858
    |
    Published online on: August 29, 2016
       https://doi.org/10.3892/ijo.2016.3673
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Abstract

The ubiquitin-proteasome and autophagy-lysosome pathways are two major self-digestive systems for cellular proteins. Ubiquitinated misfolded proteins are degraded mostly by proteasome. However, when ubiquitinated proteins accumulate beyond the capacity of proteasome clearance, they are transported to the microtubule-organizing center (MTOC) along the microtubules to form aggresomes, and subsequently some of them are degraded by the autophagy-lysosome system. We previously reported that macrolide antibiotics such as azithromycin and clarithromycin block autophagy flux, and that concomitant treatment with the proteasome inhibitor bortezomib (BZ) and macrolide enhances endoplasmic reticulum (ER) stress-mediated apoptosis in breast cancer cells. As ubiquitinated proteins are concentrated at the aggresome upon proteasome failure, we focused on the microtubule as the scaffold of this transport pathway for aggresome formation. Treatment of metastatic breast cancer cell lines (e.g., MDA-MB‑231 cells) with BZ resulted in induction of aggresomes, which immunocytochemistry detected as a distinctive eyeball-shaped vimentin-positive inclusion body that formed in a perinuclear lesion, and that electron microscopy detected as a sphere of fibrous structure with some dense amorphous deposit. Vinorelbine (VNR), which inhibits microtubule polymerization, more effectively suppressed BZ-induced aggresome formation than paclitaxel (PTX), which stabilizes microtubules. Combined treatment using BZ and VNR, but not PTX, enhanced the cytotoxic effect and apoptosis induction along with pronounced ER stress loading such as upregulation of GRP78 and CHOP/GADD153. The addition of azithromycin to block autophagy flux in the BZ plus VNR-containing cell culture further enhanced the cytotoxicity. These data suggest that suppression of BZ-induced aggresome formation using an inhibitory drug such as VNR for microtubule polymerization is a novel strategy for metastatic breast cancer therapy.
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Copy and paste a formatted citation
Spandidos Publications style
Miyahara K, Kazama H, Kokuba H, Komatsu S, Hirota A, Takemura J, Hirasawa K, Moriya S, Abe A, Hiramoto M, Hiramoto M, et al: Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines. Int J Oncol 49: 1848-1858, 2016.
APA
Miyahara, K., Kazama, H., Kokuba, H., Komatsu, S., Hirota, A., Takemura, J. ... Miyazawa, K. (2016). Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines. International Journal of Oncology, 49, 1848-1858. https://doi.org/10.3892/ijo.2016.3673
MLA
Miyahara, K., Kazama, H., Kokuba, H., Komatsu, S., Hirota, A., Takemura, J., Hirasawa, K., Moriya, S., Abe, A., Hiramoto, M., Ishikawa, T., Miyazawa, K."Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines". International Journal of Oncology 49.5 (2016): 1848-1858.
Chicago
Miyahara, K., Kazama, H., Kokuba, H., Komatsu, S., Hirota, A., Takemura, J., Hirasawa, K., Moriya, S., Abe, A., Hiramoto, M., Ishikawa, T., Miyazawa, K."Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines". International Journal of Oncology 49, no. 5 (2016): 1848-1858. https://doi.org/10.3892/ijo.2016.3673
Copy and paste a formatted citation
x
Spandidos Publications style
Miyahara K, Kazama H, Kokuba H, Komatsu S, Hirota A, Takemura J, Hirasawa K, Moriya S, Abe A, Hiramoto M, Hiramoto M, et al: Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines. Int J Oncol 49: 1848-1858, 2016.
APA
Miyahara, K., Kazama, H., Kokuba, H., Komatsu, S., Hirota, A., Takemura, J. ... Miyazawa, K. (2016). Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines. International Journal of Oncology, 49, 1848-1858. https://doi.org/10.3892/ijo.2016.3673
MLA
Miyahara, K., Kazama, H., Kokuba, H., Komatsu, S., Hirota, A., Takemura, J., Hirasawa, K., Moriya, S., Abe, A., Hiramoto, M., Ishikawa, T., Miyazawa, K."Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines". International Journal of Oncology 49.5 (2016): 1848-1858.
Chicago
Miyahara, K., Kazama, H., Kokuba, H., Komatsu, S., Hirota, A., Takemura, J., Hirasawa, K., Moriya, S., Abe, A., Hiramoto, M., Ishikawa, T., Miyazawa, K."Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines". International Journal of Oncology 49, no. 5 (2016): 1848-1858. https://doi.org/10.3892/ijo.2016.3673
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