Abstract
For many unresectable carcinomas and locally recurrent cancers (LRC), 125I seeds brachytherapy is a feasible, effective, and safe treatment. Several studies have shown that 125I seeds radiation exerts anticancer activity by triggering DNA damage. However, recent evidence shows mitochondrial quality to be another crucial determinant of cell fate, with mitophagy playing a central role in this control mechanism. Herein, we found that 125I seeds irradiation injured mitochondria, leading to significantly elevated mitochondrial and intracellular ROS (reactive oxygen species) levels in HCT116 cells. The accumulation of mitochondrial ROS increased the expression of HIF-1α and its target genes BINP3 and NIX (BINP3L), which subsequently triggered mitophagy. Importantly, 125I seeds radiation induced mitophagy promoted cells survival and protected HCT116 cells from apoptosis. These results collectively indicated that 125I seeds radiation triggered mitophagy by upregulating the level of ROS to promote cellular homeostasis and survival. The present study uncovered the critical role of mitophagy in modulating the sensitivity of tumor cells to radiation therapy and suggested that chemotherapy targeting on mitophagy might improve the efficiency of 125I seeds radiation treatment, which might be of clinical significance in tumor therapy.
Highlights
Due to its low complication rates and high efficacy—which is comparable to that of radical surgery and external beam radiation therapy—125I seeds implantation brachytherapy has become one of the most popular treatment modalities for many unresectable carcinomas and locally recurrent cancers [1,2,3,4,5,6,7]
To investigate how autophagy affects the radiosensitivity of tumor cells, clonogenic survival assay was performed to assess the response to 125I seeds radiation with and without pretreatment with autophagy inhibitors
We found that the proportion of propidium iodide (PI)−/Annexin V+ and PI+/ Annexin V+ cell population in HCT116 cells increased from 13.9% to 19.5% following treatment with 125I seeds radiation plus the autophagy inhibitor 3-MA (p ≤ 0.05, Figures 2(a) and 2(b))
Summary
Due to its low complication rates and high efficacy—which is comparable to that of radical surgery and external beam radiation therapy—125I seeds implantation brachytherapy has become one of the most popular treatment modalities for many unresectable carcinomas and locally recurrent cancers [1,2,3,4,5,6,7]. A series of studies have explored the molecular mechanisms through which 125I seeds radiation exerts anticancer activity. Most studies have focused on apoptosis and cell cycle arrest resulting from DNA damage after exposure to 125I seeds radiation [8,9,10]. There is growing evidence that mitochondria, which account for up to 30% of the total cell volume, may be important extranuclear mediators of the cytotoxic effects of radiation [11, 12]. Healthy mitochondria act as powerhouses, producing energy for cell function through the TCA cycle (tricarboxylic acid cycle) and oxidative phosphorylation [13]. Damage to mitochondria can lead to cell death and a variety of other problems [14]
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