Targeting FASN for Breast Cancer Treatment by Repositioning PPIs
Abstract
Human fatty acid synthase (FASN) is the sole cytosolic enzyme responsible for de novo synthesis of palmitate. Recently, it was found that FASN up-regulation contributes to drug and radiation resistance. It has also been found that breast cancers with high level of FASN are 4 times more likely to recur and metastasize than the ones without FASN. We recently found that proton pump inhibitors (PPIs) may inhibit FASN and, thus, possibly can be repurposed as cancer therapeutics. The working hypotheses to be tested in this grant are that FASN over-expression causes drug resistance by up-regulating repair of drug-induced DNA damages and that PPIs may be repositioned as breast cancer drugs by targeting and inhibiting FASN. Three specific aims will be accomplished. In the first year of study, we have shown that FASN up-regulates the expression of SP1 but down-regulates the expression of NF-B. Both SP1 and NF-B regulates the expression of PARP1, which, in turn possibly regulates DNA repair activity in response to DNA-damaging drugs such as doxorubicin. We also showed that PPIs dose-dependently inhibit the activity of cellular FASN. In year 2, we will determine how FASN regulates the expression of SP1 and NF-kB and the role of PARP-1 in drug resistance as well as analyze electronic medical records of breast cancer patients for the advantage of PPI use.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2017
- Accession Number
- AD1035028
Entities
People
- Jian-Ting Zhang
Organizations
- Indiana University Bloomington