All-trans-Retinoic acid (RA) is a potent anti-carcinogenic agent that functions by regulating the expression of multiple genes through its ability to activate two transcription factors: RAR and PPARd. General use of RA in oncology is hindered by the development of RA-resistance in some tumors. Moreover, in some cancers, RA treatment not only fails to inhibit carcinoma cell growth but, paradoxically, facilitates tumor development. RA is able to exert opposing effects on cell growth through alternate activation of its two receptors. The hormone inhibits growth and displays anti-carcinogenic activities when it is directed to RAR, but it enhances survival and proliferation in cells in which it is steered to PPARd. 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: cellular retinoic acid binding protein II (CRABP-II), which delivers RA to RAR, and fatty acid binding protein 5 (FABP5), which transports it to PPARd. We have identified a naturally occurring fatty acid as a small-molecule inhibitor of FABP5 that redirects RA from PPARd to RAR. Our data show that this compound suppresses cell growth in FABP5 and RA dependent manners; that it does so by increasing apoptosis, cell cycle arrest, and cell differentiation; and that it slows the growth of tumors in vivo. These results suggest that small molecule inhibitors for FABP5 could ultimately yield a novel class of anti-cancer molecules to synergize with RA.

Inhibition of fatty acid binding protein 5 suppresses mammary carcinoma cell growth in a retinoic acid dependent manner

248th National Meeting (2014)

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