The Role of UCP2 in Pancreatic Cancer Metabolism and Its Potential as a Radiosensitizer

Uncoupling protein 2 (UCP2) is a mitochondrial protein that regulates the flow of protons down the gradient established by the electron transport chain (ETC) without generating ATP, thus uncoupling the proton gradient from ATP generation. In tumors, specifically pancreatic cancer (PDAC), the ETC is highly stimulated to generate the copious ATP needed by the tumor to grow. However, extended ETC use increases reactive oxygen species (ROS), and if left unchecked, results in cell death. To evade this, PDAC employs antioxidant strategies, including upregulating UCP2 in tumor cells. In addition to its uncoupling function, UCP2 indirectly controls ROS levels by maintaining an optimal proton gradient in the ETC, keeping electrons flowing quickly through the ETC, and minimizing the chance for electrons to leak out, react with oxygen, and generate ROS. Thus, UCP2 upregulation is vital for PDAC growth and metastasis, however, targeting UCP2 for a novel tumor-specific therapeutic in PDAC has not been fully explored. PDAC has a dearth of treatment options; there are currently no FDA-approved targeted therapies, and immunotherapy is ineffective due to PDAC’s cold immune environment. In addition, chemotherapies have limited efficacy as a monotherapy and can significantly impact patient quality of life in combination with other chemotherapies. Currently, radiation therapy (RT) is the best treatment option for PDAC, but dose escalation is limited due to the pancreas’ proximity to radiosensitive organs. Thus, there is an unmet clinical need to discover novel therapy targets, ideally in combination with RT. This dissertation investigates UCP2’s potential as a therapeutic target in PDAC via mitochondrial dynamics and as a conventional radiosensitizer, and also explores the impact of ultra-high dose rate radiation on mitochondrial biology to determine the future potential for UCP2 radiosensitization with other radiation modalities. These studies reveal that while UCP2 is not a target for mitochondrial dynamics, it is a promising radiosensitizer for PDAC and it is conceivable to extend this to other radiation modalities. This work unveils a novel therapeutic target for PDAC that could expand therapy options for patients, increasing the survival of this otherwise devastating disease.