Cysteine Depletion Induces Pancreatic Tumor Ferroptosis in Mice

Overview

Journal Science

Specialty Science

Date 2020 Apr 4

PMID 32241947

Citations 525

Authors

Michael A Badgley

Daniel M Kremer

H Carlo Maurer

Kathleen E DelGiorno

Ho-Joon Lee

Vinee Purohit

Irina R Sagalovskiy

Alice Ma

Jonathan Kapilian

Christina E M Firl

Amanda R Decker

Steve A Sastra

Carmine F Palermo

Leonardo R Andrade

Peter Sajjakulnukit

Li Zhang

Zachary P Tolstyka

Tal Hirschhorn

Candice Lamb

Tong Liu

Wei Gu

E Scott Seeley

Everett Stone

George Georgiou

Uri Manor

Alina Iuga

Geoffrey M Wahl

Brent R Stockwell

Costas A Lyssiotis

Kenneth P Olive

Affiliations

Soon will be listed here.

Abstract

Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system x is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system x subunit, , induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.

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