IRG1/Itaconate induces metabolic reprogramming to suppress ER-positive breast cancer cell growth

Hsueh-Chun Wang; Wei-Chao Chang; Der-Yen Lee; Xing-Guo Li; Mien-Chie Hung

IRG1/Itaconate induces metabolic reprogramming to suppress ER-positive breast cancer cell growth

Am J Cancer Res. 2023 Mar 15;13(3):1067-1081. eCollection 2023.

Authors

Hsueh-Chun Wang^{1

2}, Wei-Chao Chang^{2

3}, Der-Yen Lee⁴, Xing-Guo Li^{1

2

5}, Mien-Chie Hung^{1

5}

Affiliations

¹ Graduate Institute of Biomedical Sciences, China Medical University Taichung 406040, Taiwan.
² Research Center for Cancer Biology, China Medical University Taichung 406040, Taiwan.
³ Center for Molecular Medicine, China Medical University Hospital, China Medical University Taichung 406040, Taiwan.
⁴ Graduate Institute of Integrated Medicine, China Medical University Taichung 406040, Taiwan.
⁵ Institute of Biochemistry and Molecular Biology, China Medical University Taichung 406040, Taiwan.

PMID: 37034222
PMCID: PMC10077032

Abstract

Most breast cancers are estrogen receptor (ER)-positive, targeted by endocrine therapies, but chemoresistance remains a significant challenge in treating the disease. Altered intracellular metabolite has closely connected with the pathogenic process of breast cancer and drug resistance. Itaconate is an anti-inflammatory metabolite generated from converting cis-aconitate in the tricarboxylic acid (TCA) cycle by the immune response gene 1 (IRG1). However, the potential role of IRG1/Itaconate in the crosstalk of metabolic pathways and tumor development is currently unknown. We tested the hypothesis that IRG1/Itaconate controls metabolic homeostasis to modulate breast cancer cell growth. We showed that breast cancers harboring an IRG1 deletion displayed a worse prognosis than those without IRG1 deletion; approximately 70% of breast cancer with IRG1 deletion were ER-positive. There was no significant difference in the IRG1 copy number, mRNA, and protein levels between ER-positive and ER-negative breast cancer cell lines and breast tumors. Itaconate selectively inhibited ER-positive breast cancer cell growth via the blockade of DNA synthesis and the induction of apoptosis. Mechanistically, IRG1 overexpression led to decreased intermediate levels of glycolysis, the TCA cycle, and lipid metabolism to compromise the entire biomass and energy of the cell. Itaconate inhibited the enzymatic activity of succinate dehydrogenase (SDH) in the mitochondrial electron-transport chain, concomitant with reactive oxygen species (ROS) production and the decreased adenylate kinase (AK) activities, which, in turn, induced AMP-activated protein kinase (AMPK) activation to restore metabolic homeostasis. These results suggest a new regulatory pathway whereby IRG1/Itaconate controls metabolic homeostasis in ER-positive breast cancer cells, which may contribute to developing more efficacious therapeutic strategies for breast cancer.

Keywords: Breast cancer; estrogen receptor; immune response gene 1; itaconate; metabolic reprogramming; tricarboxylic acid cycle.