TY - JOUR TI - Proton pump inhibitors suppress DNA damage repair and sensitize treatment resistance in breast cancer by targeting fatty acid synthase AU - Wang, Chao J. AU - Li, Deren AU - Danielson, Jacob A. AU - Zhang, Evan H. AU - Dong, Zizheng AU - Miller, Kathy D. AU - Li, Lang AU - Zhang, Jian-Ting AU - Liu, Jing-Yuan T2 - Cancer Letters AB - Human fatty acid synthase (FASN) is the sole cytosolic enzyme responsible for de novo lipid synthesis. FASN is essential for cancer cell survival and contributes to drug and radiation resistance by up-regulating DNA damage repair but not required for most non-lipogenic tissues. Thus, FASN is an attractive target for drug discovery. However, despite decades of effort in targeting FASN, no FASN inhibitors have been approved due to poor pharmacokinetics or toxicities. Here, we show that the FDA-approved proton pump inhibitors (PPIs) effectively inhibit FASN and suppress breast cancer cell survival. PPI inhibition of FASN leads to suppression of non-homologous end joining repair of DNA damages by reducing FASN-mediated PARP1 expression, resulting in apoptosis from oxidative DNA damages and sensitization of cellular resistance to doxorubicin and ionizing radiation. Mining electronic medical records of 6754 breast cancer patients showed that PPI usage significantly increased overall survival and reduced disease recurrence of these patients. Hence, PPIs may be repurposed as anticancer drugs for breast cancer treatments by targeting FASN and to overcome drug and radiation resistance. DA - 2021/04/01/ PY - 2021 DO - 10.1016/j.canlet.2021.03.026 DP - ScienceDirect J2 - Cancer Letters LA - en SN - 0304-3835 UR - https://www.sciencedirect.com/science/article/pii/S030438352100149X Y2 - 2021/04/08/00:04:59 KW - DNA damage Repair KW - Enantiomer KW - Fatty acid synthase KW - PARP1 KW - Proton pump inhibitor ER -