Fractalkine Receptor Regulates Cellular Response to X-Ray Radiation in Ovarian Cancer Cells
2016-02-17T00:00:00Z (GMT) by
High-grade serous carcinoma (HGSC) is the most common and lethal histotype of ovarian cancer. Radiation is usually used as a second-line treatment against the disease. In spite of numerous clinical studies indicating efficacy of radiation therapy in patients suffering from disease recurrence, it is seldom used clinically due to severe dose-related toxicity. Discovery and utilization of novel radiosensitizers could control the toxicity and enable effective therapeutic application of radiation. Fractalkine receptor (CX3CR1) belongs to a chemokine family of G protein-coupled receptors. Our previous publications showed that CX3CR1 is not expressed in normal ovarian surface epithelium and is expressed in primary and metastatic epithelial ovarian carcinoma. Moreover, transient downregulation of CX3CR1 in ovarian cancer cells will impair their proliferation as well as their migration and adhesion to peritoneal mesothelial cells. Therefore, we proposed combining CX3CR1 downregulation and radiation as a strategy for reducing the dose of radiation while maintaining the therapeutic efficacy. The experimental observations indicated that transient downregulation of CX3CR1 in most HGSC cell lines can lead to radiosensitization, as determined by clonogenic assay. However, loss of CX3CR1 does not affect radiosensitivity in ovarian cancer cells that express wild-type p53. There are several altered characteristics that may contribute to resistance to ionizing radiation, including enhanced DNA damage repair, and adaptive response to the radiation-induced ROS (Reactive Oxygen Species). Specifically, my results indicated that downregulation of CX3CR1 can abrogate the phosphorylation and activation of DNA double-strand break repair related proteins following ionizing radiation. The unrepaired DNA damage leads to damage persistence and ultimately contributes to radiosensitization. Another mechanism by which CX3CR1 knockdown alters radiosensitivity is the regulation of cellular redox capacity, where loss of CX3CR1 leads to elevated ROS levels. Taken together, my study demonstrated for the novel findings that loss of CX3CR1 can sensitize HGSC cells to ionizing radiation through the regulation of DNA damage response and intracellular redox status.