Oncotarget

Research Papers:

Sensitization of tamoxifen-resistant breast cancer cells by Z-ligustilide through inhibiting autophagy and accumulating DNA damages

Hongyi Qi _, Zhuyun Jiang, Chengqiang Wang, Yi Yang, Li Li, Hui He and Zanyang Yu

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Oncotarget. 2017; 8:29300-29317. https://doi.org/10.18632/oncotarget.16832

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Abstract

Hongyi Qi1,*, Zhuyun Jiang1,*, Chengqiang Wang1, Yi Yang1, Li Li1, Hui He1, Zanyang Yu1

1College of Pharmaceutical Sciences, Southwest University, Beibei District, Chongqing 400716, China

*These authors have contributed equally to this work

Correspondence to:

Hongyi Qi, email: hongyiqi@swu.edu.cn

Keywords: Z-ligustilide, tamoxifen, autophagic flux, chemoresistance, DNA damage

Received: February 21, 2017     Accepted: March 26, 2017     Published: April 04, 2017

ABSTRACT

Autophagy plays a pro-survival role in the tamoxifen-resistant breast cancer cells. Herein we found that autophagy was concomitantly induced in tamoxifen-resistant MCF-7 (MCF-7TR5) cells through the dissociation of Bcl-2 from Beclin 1 and subsequent enhancement of interaction among the ATG14-Beclin1-PI3KC3 complex. Moreover, higher level of DNA damage was observed in MCF-7TR5 cells with the decreased BRCA1 and RAD51 level and the increased Ku80 level. Interestingly, Nur77 was selectively degraded by autophagy, which causes the release of Ku80 from the Nur77-Ku80 complex, resulting in the increase of the DNA binding of Ku80 and DNA-PKcs. Meanwhile, Z-ligustilide, a phthalide compound from Radix Angelica sinensis, was shown to inhibit the autophagic flux by blocking the autophagosome-lysosome fusion. Importantly, Z-ligustilide-mediated autophagy inhibition restored Nur77 expression in MCF-7TR5 cells. Furthermore, Z-ligustilide promoted the interaction of Nur77 with Ku80 and thereby abolished the association of DNA-PKcs with DNA ends. Moreover, Z-ligustilide sensitized MCF-7TR5 cells in a caspase-independent cell death and enhanced the DNA damage caused by tamoxifen, which was found to be attenuated by shNur77. Together, these findings not only provide important insights into the formation of tamoxifen resistance in breast cancer cells, but also suggest Z-ligustilide may function as a novel autophagy inhibitor to overcome chemoresistance.


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