This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Identifying potent novel drugs and therapeutic treatments to combat the myriad of cancers requires decades of investigation. The objective of this research project is to use Saccharomyces cerevisiae (budding yeast) as a screening tool to quickly identify potential molecular targets of the putative, novel anti-cancer drug, fusarochromanone (FC-101) and its analogues. FC-101 is a small natural flavonoid compound and mycotoxin produced by Fusarium equiseti, a fungus present in decaying cereal plants. Studies indicate that FC-101 increases apoptosis of melanomas and reduces tumor growth in vitro and in vivo. To date, the molecular mechanisms by which this compound elicits its anti-tumor effects are largely unknown. To that end, we are employing yeast molecular genetics strategies to identify its molecular target. In this study, we found that 0.343 mM FC-101 inhibits the growth rate of wild-type cells by 50%. Furthermore, we have determined that cells containing a deletion of MCA1/YCA1 are hypersensitive to FC-101. YCA1 encodes a metacaspase, which is required to regulate cell cycle progression in yeast. We hypothesize that YCA1 may represent an FC-101-specific molecular target. Currently, we are screening of the yeast deletion collection of non-essential genes for additional strains that are resistant or hypersensitive to FC-101. Future studies may include assessing the genetic interactions of genes involved in a potential FC-101-specific pathways and assessing differential expression in wild-type cells exposed to FC-101. We anticipate that this study will serve as an important first step toward the development of FC-101 as a prospective chemotherapeutic drug.
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