Retinoic acid (RA) is a potent anticarcinogenic agent that functions by regulating the expression of multiple genes through its ability to activate two transcription factors: RAR and PPARDELTA. However, its utility as a therapeutic agent is limited by RA-resistance that is acquired in some tumors. Activation of RAR results in inhibition of cancer cell growth, while activation of PPARDELTA leads to enhanced growth and survival. The key to regulating the partitioning of RA between these two opposing pathways lies in the two proteins that deliver RA to their respective transcription factors: CRABP-II, which delivers RA to RAR, and FABP5, which transports it to PPARDELTA. Hence, cells that express a high level of FABP5 become resistant to RA-induced growth inhibition and, instead, display enhanced proliferation in response to RA. The goal of this work is to further investigate this partitioning between RAR and PPARDELTA using naturally occurring retinoids and fatty acids as probes. Moreover, this projects aims to develop a small molecule inhibitor(s) for FABP5 which could ultimately yield a novel class of anticarcinogenic molecules to synergize with RA.

Public Health Relevance

This research will provide significant insights into the mechanism of development of retinoic acid (RA) resistance in some cancers. RA resistance is thought to develop as a result of two competing pathways, one which inhibits cancer cell growth and another which leads to enhanced growth and survival of cancer cells. The goal of this work is to further investigate this partitioning between these two pathways using naturally occurring compounds as probes. Moreover, this projects aims to develop a small molecule inhibitor which could ultimately yield a novel class of anti-carcinogenic therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA165599-03
Application #
8700346
Study Section
Special Emphasis Panel (ZRG1-F04B-D (20))
Program Officer
Korczak, Jeannette F
Project Start
2012-08-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$42,676
Indirect Cost
Name
Case Western Reserve University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106