This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The objective of this project is to use Saccharomyces cerevisiae (budding yeast) and human cancer cell lines to identify the molecular target(s) of a putative anti-cancer drug, fusarochromanone (FC-101a). FC-101a is a mycotoxin produced by Fusarium equiseti, which causes plant diseases such as wilt, scab, and rot. Studies performed at the National Cancer Institute revealed that FC-101a is a potent inhibitor of 35 human cancer cell lines. Recent studies indicate that FC-101a increases apoptosis in melanoma cell lines and significantly reduces tumor growth in mice. To understand the molecular mechanisms by which this drug acts to elicit its anti-tumor effects, we performed a genetic screen of the yeast deletion collection, which revealed that a YCA1 gene deletion strain is hypersensitive to FC-101a. YCA1 encodes the yeast metacaspase that initiates an apoptosis-like response and participates in the mitotic G2/M checkpoint. We hypothesize that FC-101a may target gene products that regulate cell cycle progression and/or apoptosis. Currently, we are classifying genes that are differentially expressed in yeast and a bladder cancer cell line with greater than 70% growth inhibition after treatment with 100 nM FC-101a. From this cell line we have identified genes that are differentially expressed after 24, 48 and 72 hours of FC-101a treatment. Future studies will involve isolating proteins that interact with FC-101a. Putative molecular targets of FC-101a identified in yeast and human cancer cell lines will be validated in animal model studies.
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