Hydrogen Peroxide Promotes the Production of Radiation-Derived EVs Containing Mitochondrial Proteins

作者：Caitlin Miller, Fangfang Xu, Yanming Zhao, Wei Luo, Weixiong Zhong, Kristy Meyer, Rani Jayswal, Heidi L. Weiss, William H. St. Clair, Daret K. St. Clair, Luksana Chaiswing · 发表于：Antioxidants · 年份：2022 · DOI：10.3390/antiox11112119 · 被引用次数：13 · 研究领域：Mitochondrial Function and Pathology、Redox biology and oxidative stress、Heat shock proteins research

In spite of extensive successes, cancer recurrence after radiation treatment (RT) remains one of the significant challenges in the cure of localized prostate cancer (PCa). This study focuses on elucidating a novel adaptive response to RT that could contribute to cancer recurrence. Here, we used PC3 cell line, an adenocarcinoma from a bone metastasis and radio-resistant clone 695 cell line, which survived after total radiation dose of 66 Gy (2 Gy × 33) and subsequently regrew in nude mice after exposure to fractionated radiation at 10 Gy (2 Gy × 5). Clone 695 cells not only showed an increase in surviving fraction post-radiation but also an increase in hydrogen peroxide (H2O2) production when compared to PC3 cells. At the single cell level, confocal microscope images coupled with IMARIS rendering software demonstrate an increase in mitochondrial mass and membrane potential in clone 695 cells. Utilizing the Seahorse XF96 instrument to investigate mitochondrial respiration, clone 695 cells demonstrated a higher basal Oxygen Consumption Rate (OCR), ATP-linked OCR, and proton leak compared to PC3 cells. The elevation of mitochondrial function in clone 695 cells is accompanied by an increase in mitochondrial H2O2 production. These data suggest that H2O2 could reprogram PCa’s mitochondrial homeostasis, which allows the cancer to survive and regrow after RT. Upon exposure to RT, in addition to ROS production, we found that RT induces the release of extracellular vesicles (EVs) from P...