Distinct TP53 Mutation Subtypes Differentially Influence Cellular Iron Metabolism

Stephen L Clarke,Mckale R Montgomery,Eshan Dandekar,Laurie R Thompson,Aishwarya Srinivasan

doi:10.3390/nu11092144

Stephen L Clarke, Mckale R Montgomery + Show 3 more

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https://doi.org/10.3390/nu11092144

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Journal: Nutrients	Publication Date: Sep 7, 2019
Citations: 12	License type: CC BY 4.0

Affiliation: Oklahoma State University

Abstract

The most commonly mutated gene in all human cancers is the tumor suppressor gene TP53; however, in addition to the loss of tumor suppressor functions, mutations in TP53 can also promote cancer progression by altering cellular iron acquisition and metabolism. The primary objective of this work was to determine how TP53 mutation status influences the molecular control of iron homeostasis. The effect of TP53 mutation type on cellular iron homeostasis was examined using cell lines with inducible versions of either wild-type TP53 or a representative mutated TP53 gene from exemplary “hotspot” mutations in the DNA binding domain (R248, R273, and R175) as well as H193Y. The introduction of distinct TP53 mutation types alone was sufficient to disrupt cellular iron metabolism. These effects were mediated, at least in part, due to differences in the responsiveness of iron regulatory proteins (IRPs) to cellular iron availability. IRPs are considered the master regulators of intracellular iron homeostasis because they coordinate the expression of iron storage (ferritin) and iron uptake (transferrin receptor) genes. In response to changes in iron availability, cells harboring either a wild-type TP53 or R273H TP53 mutation displayed canonical IRP-mediated responses, but neither IRP1 RNA binding activity nor IRP2 protein levels were affected by changes in iron status in cells harboring the R175H mutation type. However, all mutation types exhibited robust changes in ferritin and transferrin receptor protein expression in response to iron loading and iron chelation, respectively. These findings suggest a novel, IRP-independent mode of iron regulation in cells expressing distinct TP53 mutations. As TP53 is mutated in nearly half of all human cancers, and iron is necessary for cancer cell growth and proliferation, the studies have implications for a wide range of clinically important cancers.

Highlights

The essentiality of iron for cell growth and proliferation, coupled with its capacity to promote damaging free radical production, has made it a desirable target for cancer treatment and prevention.distinct iron-related gene expression patterns are associated with both the development of metastases and patient survival [1,2,3,4]
We demonstrate that the introduction of distinct TP53 mutation types alone is sufficient to significantly and differentially alter total cellular iron levels as well as spontaneous iron regulatory proteins (IRPs) RNA binding activity
The tumor suppressor TP53 is the most commonly mutated gene in human cancers, and iron is is necessary for cancer cell growth and proliferation, but there is a paucity of data delineating the necessary for cancer cell growth and proliferation, but there is a paucity of data delineating the contribution of TP53 mutations to the regulation of iron homeostasis

Summary

Introduction

The essentiality of iron for cell growth and proliferation, coupled with its capacity to promote damaging free radical production, has made it a desirable target for cancer treatment and prevention.distinct iron-related gene expression patterns are associated with both the development of metastases and patient survival [1,2,3,4]. The essentiality of iron for cell growth and proliferation, coupled with its capacity to promote damaging free radical production, has made it a desirable target for cancer treatment and prevention. It is important to first understand how cancer cells manipulate the homeostatic regulators of iron metabolism to promote malignancy before we can fully harness iron’s therapeutic potential. One such mechanism may be through the acquisition of TP53 mutations. Cells that lack TP53, or express a mutant TP53, accumulate iron in response to DNA damage [5]. Mutations in TP53 have been shown to decrease tumor cell responsiveness to iron restriction [6]. The inactivation of iron regulatory proteins can facilitate wild-type

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