Insights into low dose irradiation-induced mitochondrial ROS signaling in human breast cancer cells

Details

Supervisors

Sonveaux, Pierre ; Rondeau, Justin

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Breast cancer is a prevalent disease in women worldwide. Standard treatment involves X-ray radiotherapy, damaging cancer cell DNA through the production of reactive oxygen species (ROS), ultimately leading to cell death. However, the current clinical technology does not uniformly distribute radiation doses across tumors, resulting in some cancer cells being exposed to subcytotoxic doses, known as low dose ionizing radiation (LDIR). We observed that, besides acute ROS generation resulting from water radiolysis at the whole cell level, LDIR also triggers a long-term (≥ 48 h), sustained production of mitochondrial ROS (mtROS). This is due to mitochondrial dysfunctions. Because mtROS can promote cancer cell migration, we aimed to link these two independent observations, hypothesizing that migration could be a side effect of LDIR. Using luminal A MCF7 and triple-negative MDA-MB-231 human breast cancer cells as models, we confirmed, using a mitochondria-targeted HyPer fluorescent system reporting on mtH2O2, that LDIR (0.5 and 0.125 Gy, respectively) stimulated mtH2O2 production. To further test a causal link between enhanced mtH2O2 production and cancer cell migration, we took advantage of D-amino acid oxidase (DAAO) converting exogenously delivered D-alanine (but not L-alanine) to an imino derivative + H2O2 selectively within mitochondria. Dose testing showed that 10 mM of D-alanine was the optimal concentration for mtH2O2 generation in our cell models. Phenotypically, it induced cell migration. Combining LDIR and D-alanine had no additive effect on cell migration, probably because a plateau of mtROS concentration was reached. The treatments and their combination did not trigger cancer cell death. Overall, this research contributes to a better understanding of the cellular mechanisms underlying the effects of LDIR on human breast cancer cells. In particular, we found that LDIR sequentially increases subcytotoxic mtROS generation and cancer cell migration, which could be inhibited using mitochondria-targeted antioxidants.