Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmic reticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells

  • Authors:
    • Seiichiro Komatsu
    • Keisuke Miyazawa
    • Shota Moriya
    • Akiko Takase
    • Munekazu Naito
    • Masato Inazu
    • Norio Kohno
    • Masahiro Itoh
    • Akio Tomoda
  • View Affiliations

  • Published online on: December 23, 2011     https://doi.org/10.3892/ijo.2011.1317
  • Pages: 1029-1039
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Abstract

The specific 26S proteasome inhibitor, bortezomib (BZ) potently induces apoptosis as well as autophagy in metastatic breast cancer cell lines such as MDA-MB-231 and MDA-MB-468. The combined treatment of clarithromycin (CAM) and BZ significantly enhances cytotoxicity in these cell lines. Although treatment with up to 100 µg/ml CAM alone had little effect on cell growth inhibition, the accumulation of autophagosomes and p62 was observed after treatment with 25 µg/ml CAM. This result indicated that CAM blocked autophagy flux. However, the combined treatment of BZ and CAM resulted in more pronounced autophagy induction, as assessed by increased expression ratios of LC3B-II to LC3B-I and clearance of intracellular p62, than treatment with BZ alone. This combination further enhanced induction of the pro-apoptotic transcription factor CHOP (CADD153) and the chaperone protein GRP78. Knockdown of CHOP by siRNA attenuated the death-promoting effect of BZ in MDA-MB-231 cells. A wild-type murine embryonic fibroblast (MEF) cell line also exhibited enhanced BZ-induced cytotoxicity with the addition of CAM, whereas a Chop knockout MEF cell line completely abolished this enhancement and exhibited resistance to BZ treatment. These data suggest that endoplasmic reticulum (ER)-stress mediated CHOP induction is involved in pronounced cytotoxicity by combining these reagents. Simultaneously targeting two major intracellular protein degradation pathways such as the ubiquitin-proteasome system by BZ and the autophagy-lysosome pathway by CAM may improve the therapeutic outcome in breast cancer patients via ER-stress mediated apoptosis.
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April 2012
Volume 40 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Komatsu S, Miyazawa K, Moriya S, Takase A, Naito M, Inazu M, Kohno N, Itoh M and Tomoda A: Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmic reticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells. Int J Oncol 40: 1029-1039, 2012
APA
Komatsu, S., Miyazawa, K., Moriya, S., Takase, A., Naito, M., Inazu, M. ... Tomoda, A. (2012). Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmic reticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells. International Journal of Oncology, 40, 1029-1039. https://doi.org/10.3892/ijo.2011.1317
MLA
Komatsu, S., Miyazawa, K., Moriya, S., Takase, A., Naito, M., Inazu, M., Kohno, N., Itoh, M., Tomoda, A."Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmic reticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells". International Journal of Oncology 40.4 (2012): 1029-1039.
Chicago
Komatsu, S., Miyazawa, K., Moriya, S., Takase, A., Naito, M., Inazu, M., Kohno, N., Itoh, M., Tomoda, A."Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmic reticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells". International Journal of Oncology 40, no. 4 (2012): 1029-1039. https://doi.org/10.3892/ijo.2011.1317