NUCLEAR RECEPTOR LIGAND TARGETING BY THE FATTY ACID BINDING PROTEINS: IMPLICATION

Case Western Reserve University, Cleveland OH

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Abstract

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.