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.
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.
| Hofmann, Lukas; Tsybovsky, Yaroslav; Alexander, Nathan S et al. (2016) Structural Insights into the Drosophila melanogaster Retinol Dehydrogenase, a Member of the Short-Chain Dehydrogenase/Reductase Family. Biochemistry 55:6545-6557 |
| Levi, Liraz; Lobo, Glenn; Doud, Mary Kathryn et al. (2013) Genetic ablation of the fatty acid-binding protein FABP5 suppresses HER2-induced mammary tumorigenesis. Cancer Res 73:4770-80 |
