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

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

doi:10.18632/oncotarget.4002

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.

Highlights

Among cancers affecting in women, breast cancer has the highest incidence and causes the second highest mortality [1]
P53 was rapidly degraded under normoxic conditions when cells were treated with TAT-oxygen-dependent degradation domain557–574 (ODD)-p53, but it remained stable under hypoxic conditions (Figure 1A)
These results demonstrated that TAT-ODD-p53 penetrated the cells sufficiently and was selectively stable under hypoxic conditions

Summary

Introduction

Among cancers affecting in women, breast cancer has the highest incidence and causes the second highest mortality [1]. Current treatment for breast cancer often involves radiation therapy, which is widely used and effective. Hypoxic tumor cells usually exhibit radioresistance, which poses a challenge for successful radiation therapy [2]. Hypoxic regions are found in most solid tumors, but seldom occur in normal tissues [3, 4]. Hypoxic cells are an attractive tumor-specific target for improving the response to ionizing radiation. In some tumor cell lines, hypoxia may decrease radiosensitivity by suppression of p53 activity [7], while reactivation of p53 seems to be an effective method of targeting hypoxic tumors [8]. Because hypoxic regions are uncommon in normal tissues, synthetic p53 peptides targeting hypoxic cancer cells could provide a novel approach to radiosensitization

Methods

Results

Conclusion