Abstract 2006: The contributions of iron regulatory proteins 1 and 2 to ferroptosis activation and ferroptotic cell death

Abstract

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. One such approach may be through the activation of ferroptosis, a form of iron-mediated programmed cell death. However, we must first understand how cancer cells manipulate the homeostatic regulators of iron metabolism to promote malignancy before we can fully harness iron's therapeutic potential. The iron regulatory proteins 1 and 2 (IRP1 and IRP2) are the master regulators of intracellular iron homeostasis because they coordinate the expression of proteins involved in iron storage, uptake, and utilization. Yet, the roles and regulation of IRPs during cellular ferroptosis remain unknown. The primary objective of this work was to examine the reciprocal relationship between ferroptosis activation and IRP mRNA binding activity. Utilizing tetracycline-inducible plasmids, we found that overexpression of IRP1 or IRP2 significantly increases sensitivity to ferroptotic cell death in HEK293T cells. Intriguingly however, ferroptosis induction by erastin treatment differentially influences IRP1 and IRP2 mRNA binding activity in a cell-type dependent manner, with those cell types expressing higher levels IRP2 exhibiting increased sensitivity to ferroptosis activation. Yet, IRP2 knockout cells are still subject to ferroptotic cell death, as are cells that lack IRP1 expression. Collectively, our findings suggest that while increased expression of IRP1 and IRP2 can promote ferroptotic cell death, expression of IRP1 or IRP2 is sufficient to convey sensitivity to ferroptosis activation. To identify mechanism driving increased IRP mRNA binding activity during cellular ferroptosis, we are currently assessing both iron-dependent and -independent regulators of IRP1 and IRP2 function and stability. As iron is an essential, yet potentially toxic nutrient, such findings will be important because they are expected to provide novel insights for exploiting the toxic nature of iron without compromising the essential homeostatic control mechanisms. Citation Format: Evan Hermann, Thais Oliveira, McKale Montgomery. The contributions of iron regulatory proteins 1 and 2 to ferroptosis activation and ferroptotic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2006.