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Curcumin inhibits growth of Saccharomyces cerevisiae through iron chelation.

ABSTRACT: Curcumin, a polyphenol derived from turmeric, is an ancient therapeutic used in India for centuries to treat a wide array of ailments. Interest in curcumin has increased recently, with ongoing clinical trials exploring curcumin as an anticancer therapy and as a protectant against neurodegenerative diseases. In vitro, curcumin chelates metal ions. However, although diverse physiological effects have been documented for this compound, curcumin's mechanism of action on mammalian cells remains unclear. This study uses yeast as a model eukaryotic system to dissect the biological activity of curcumin. We found that yeast mutants lacking genes required for iron and copper homeostasis are hypersensitive to curcumin and that iron supplementation rescues this sensitivity. Curcumin penetrates yeast cells, concentrates in the endoplasmic reticulum (ER) membranes, and reduces the intracellular iron pool. Curcumin-treated, iron-starved cultures are enriched in unbudded cells, suggesting that the G(1) phase of the cell cycle is lengthened. A delay in cell cycle progression could, in part, explain the antitumorigenic properties associated with curcumin. We also demonstrate that curcumin causes a growth lag in cultured human cells that is remediated by the addition of exogenous iron. These findings suggest that curcumin-induced iron starvation is conserved from yeast to humans and underlies curcumin's medicinal properties.

SUBMITTER: Minear S

PROVIDER: S-EPMC3209049 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Curcumin inhibits growth of Saccharomyces cerevisiae through iron chelation.

Minear Steven S O'Donnell Allyson F AF Ballew Anna A Giaever Guri G Nislow Corey C Stearns Tim T Cyert Martha S MS

Eukaryotic cell 20110909 11

Curcumin, a polyphenol derived from turmeric, is an ancient therapeutic used in India for centuries to treat a wide array of ailments. Interest in curcumin has increased recently, with ongoing clinical trials exploring curcumin as an anticancer therapy and as a protectant against neurodegenerative diseases. In vitro, curcumin chelates metal ions. However, although diverse physiological effects have been documented for this compound, curcumin's mechanism of action on mammalian cells remains uncle ...[more]

PMID: 21908599

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Project description:Fermenting cells growing exponentially on rich (YPAD) medium underwent a transition to a slow-growing state as glucose levels declined and their metabolism shifted to respiration. During exponential growth, Fe import and cell-growth rates were matched, affording an approximately invariant cellular Fe concentration. During the transition period, the high-affinity Fe import rate declined slower than the cell-growth rate declined, causing Fe to accumulate, initially as Fe(III) oxyhydroxide nanoparticles but eventually as mitochondrial and vacuolar Fe. Once the cells had reached slow-growth mode, Fe import and cell-growth rates were again matched, and the cellular Fe concentration was again approximately invariant. Fermenting cells grown on minimal medium (MM) grew more slowly during the exponential phase and underwent a transition to a true stationary state as glucose levels declined. The Fe concentration of MM cells that just entered the stationary state was similar to that of YPAD cells, but MM cells continued to accumulate Fe in the stationary state. Fe initially accumulated as nanoparticles and high-spin Fe(II) species, but vacuolar Fe(III) also eventually accumulated. Surprisingly, Fe-packed 5-day-old MM cells suffered no more reactive oxygen species (ROS) damage than younger cells, suggesting that the Fe concentration alone does not accurately predict the extent of ROS damage. The mode and rate of growth at the time of harvesting dramatically affected cellular Fe content. A mathematical model of Fe metabolism in a growing cell was developed. The model included the import of Fe via a regulated high-affinity pathway and an unregulated low-affinity pathway. The import of Fe from the cytosol to vacuoles and mitochondria and nanoparticle formation were also included. The model captured essential trafficking behavior, demonstrating that cells regulate Fe import in accordance with their overall growth rate and that they misregulate Fe import when nanoparticles accumulate. The lack of regulation of Fe in yeast is perhaps unique compared to the tight regulation of other cellular metabolites. This phenomenon likely derives from the unique chemistry associated with Fe nanoparticle formation.

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Curcumin inhibits growth of Saccharomyces cerevisiae through iron chelation.

Publications

Curcumin inhibits growth of Saccharomyces cerevisiae through iron chelation.

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