Regulation of DNA damage repair and lipid uptake by CX 3 CR1 in epithelial ovarian carcinoma

摘要

Failure of currently used cytotoxic chemotherapy is one of the main reasons behind high mortality from metastatic high grade serous ovarian carcinoma. We found that high expression of a receptor for fractalkine (CX₃CR1) significantly correlated with shorter survival of patients with serous ovarian carcinoma treated with cytotoxic DNA damage chemotherapies, and reduction of CX₃CR1 expression resulted in sensitization to several DNA damaging modalities, including x-ray radiation and cisplatin. Here, we show that CX₃CR1 plays a role in double-strand DNA break response and repair by regulating expression of RAD50 by a MYC-dependent mechanism. We demonstrate that downregulation of CX₃CR1 alone and in a combination with irradiation affects peritoneal metastasis in an organ-specific manner; we show that CX₃CR1 regulates lipid uptake which could control omental metastasis. This study identifies CX₃CR1 as a novel potential target for sensitization of ovarian carcinoma to DNA damage therapies and reduction of peritoneal carcinomatosis.