Journal
MOLECULAR PHARMACOLOGY
Volume 87, Issue 5, Pages 825-831Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.114.097550
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Funding
- National Institutes of Health National Cancer Institute [K08-CA172676-02]
- Breast Cancer Research Foundation
- Sidney Kimmel Foundation for Cancer Research
- Carol M. Baldwin Breast Cancer Research Award
- National Institutes of Health National Institute of General Medical Sciences [R01-GM088403]
- Harrington Discovery Institute
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p53 is a Zn2+-dependent tumor suppressor inactivated in >50% of human cancers. The most common mutation, R175H, inactivates p53 by reducing its affinity for the essential zinc ion, leaving the mutant protein unable to bind the metal in the low [Zn2+](free) environment of the cell. The exploratory cancer drug zinc metallochaperone-1 (ZMC1) was previously demonstrated to reactivate this and other Zn2+-binding mutants by binding Zn2+ and buffering it to a level such that Zn2+ can repopulate the defective binding site, but how it accomplishes this in the context of living cells and organisms is unclear. In this study, we demonstrated that ZMC1 increases intracellular [Zn2+](free) by functioning as a Zn2+ ionophore, binding Zn2+ in the extracellular environment, diffusing across the plasma membrane, and releasing it intracellularly. It raises intracellular [Zn2+](free) in cancer (TOV112D) and noncancer human embryonic kidney cell line 293 to 15.8 and 18.1 nM, respectively, with half-times of 2-3 minutes. These [Zn2+](free) levels are predicted to result in similar to 90% saturation of p53-R175H, thus accounting for its observed reactivation. This mechanism is supported by the X-ray crystal structure of the [Zn(ZMC1)(2)] complex, which demonstrates structural and chemical features consistent with those of known metal ionophores. These findings provide a physical mechanism linking zinc metallochaperone-1 in both in vitro and in vivo activities and define the remaining critical parameter necessary for developing synthetic metallochaperones for clinical use.
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