The ability of butyrate, as a prototypic short chain fatty acid (SCFA), to arrest cells in cell cycle has been recognized for almost two decades. SCFAs produced in the colon regulate the growth of colonocytes and protect against the development of neoplasia. Currently, the butyrates and related short chain fatty acids are being used in multiple clinical trials to stimulate differentiation and death in tumor cells, to regulate developmentally-silenced genes in treatment of inherited blood disorders, and for the treatment of metabolic diseases. More recently, we have synthesized derivatives of SCFAs which promote cell growth, in a manner analogous to the protein cytokines. Yet, the biochemical and molecular mechanisms through which the SCFAs generate these diverse biological effects remain completely unknown. This is due, in part, to the number of biochemical activities attributed to the SCFAs, including histone deacetylase inhibitory activity, elevation of cyclic nucleotide levels, regulation of cellular phosphatases, and inhibition of farnesyl transferase activity, among other activities. To definitively determine the molecular mechanisms underlying the growth inhibitory and the growth promoting activities of the short chain fatty acids, we have developed a panel of SCFA derivatives which share some, but not all, of the biochemical properties of the parental compounds. We hypothesize that these compounds will allow us to dissect out precisely which biochemical properties are required for specific biological activities. In the First Specific Aim, we will determine molecular basis for the reversible G1 arrest induced by certain of the SCFAs. We have previously shown that this arrest is mediated by a signal transmitted by the Rb protein. How this signal is generated, and the mediators of this signal, will be determined. In addition, the mechanism underlying the induction of apoptosis in tumor cells by the short chain fatty acids, and their failure to arrest at the G1 checkpoint, will be determined. In the Second Specific Aim, SCFAs which are capable of inducing cell proliferation, presumably by suborning peptide growth factor pathways, will be determined. We will test the hypothesis that some of the prototypic SCFAs, like butyrate itself, actually have both anti- mitogenic and pro-mitogenic activities and that these can be biochemically isolated, using the SCFA derivatives we have synthesized. These studies will elucidate the physiological role of the SCFAs in regulating cell growth, and also provide a scientific basis for the future development of therapeutics, in that compounds can be synthesized preserving only those biochemical activities leading to the desired therapeutic effect.
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