Oncotarget

Research Papers:

TAT-ODD-p53 enhances the radiosensitivity of hypoxic breast cancer cells by inhibiting Parkin-mediated mitophagy

Rong Zheng _, Qiwei Yao, Guozhu Xie, Shasha Du, Chen Ren, Yuxia Wang and Yawei Yuan

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Oncotarget. 2015; 6:17417-17429. https://doi.org/10.18632/oncotarget.4002

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Abstract

Rong Zheng1,*, Qiwei Yao1,*, Guozhu Xie1,*, Shasha Du1, Chen Ren1, Yuxia Wang2, Yawei Yuan1

1Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China

2Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China

*These authors have contributed equally to this work

Correspondence to:

Yawei Yuan, e-mail: yuanyw66@aliyun.com

Keywords: p53, mitophagy, radiosensitivity, Parkin

Received: March 26, 2015     Accepted: May 06, 2015     Published: May 18, 2015

ABSTRACT

Radiation therapy has an important role in the treatment of breast cancer. Dysfunction p53 and hypoxia are typical biological characteristics of breast cancer that constitute barriers to the efficacy of radiotherapy. Mitophagy plays a protective role in cellular homeostasis under hypoxic conditions, while mitophagy is inhibited by p53 in normal cells. We explored the effects of a p53 fusion protein, TAT-ODD-p53, on the radiosensitivity of hypoxic breast cancer cells both in vitro and in vivo, as well as investigating the related molecular mechanisms. We found that selective accumulation of TAT-ODD-p53 occurred under hypoxic conditions and significantly increased tumor cell radiosensitivity both in vitro and in vivo. Mitophagy had an important role in maintaining hypoxia-induced radioresistance. Mitophagy was inhibited by TAT-ODD-p53 and this inhibition was suppressed by over-expression of Parkin in hypoxic irradiated breast cancer cells. In addition, mitophagy was induced by deletion of p53, with this effect being weakened by Parkin knockdown at a low oxygen tension. By interacting with Parkin, p53 inhibited the translocation of Parkin to the mitochondria, disrupting the protective mitophagy process. These results suggest that TAT-ODD-p53 has a significant and preferential radiosensitizing effect on hypoxic breast cancer cells by inhibition of Parkin-mediated mitophagy.


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