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

Hsueh-Chun Wang1,2, Wei-Chao Chang2,3, Der-Yen Lee4

  • 1Graduate Institute of Biomedical Sciences, China Medical University Taichung 406040, Taiwan.

American Journal of Cancer Research
|April 10, 2023
PubMed

Insights

Immune response gene 1 (IRG1) and its metabolite itaconate regulate metabolic homeostasis in estrogen receptor-positive breast cancer. IRG1 deletion worsens prognosis, while itaconate inhibits cancer cell growth by disrupting DNA synthesis and inducing apoptosis.

Area of Science:

  • Biochemistry
  • Oncology
  • Metabolism

Background:

  • Most breast cancers are estrogen receptor (ER)-positive and treated with endocrine therapies, but chemoresistance is a major hurdle.
  • Altered intracellular metabolites are linked to breast cancer progression and drug resistance.
  • Itaconate, an anti-inflammatory metabolite from the immune response gene 1 (IRG1), has an unknown role in tumor development and metabolic crosstalk.

Purpose of the Study:

  • To investigate the role of IRG1/Itaconate in controlling metabolic homeostasis and modulating breast cancer cell growth.
  • To test the hypothesis that IRG1/Itaconate influences metabolic pathways critical for tumor development.

Main Methods:

  • Analysis of breast cancer patient data for IRG1 deletion and prognosis.
  • Comparison of IRG1 expression levels in ER-positive and ER-negative breast cancer cell lines and tumors.
  • Assessment of itaconate's effects on ER-positive breast cancer cell growth, DNA synthesis, and apoptosis.
  • Investigation of IRG1 overexpression effects on cellular metabolism, including glycolysis, TCA cycle, and lipid metabolism.
  • Examination of itaconate's impact on mitochondrial function, reactive oxygen species (ROS) production, and key metabolic enzymes like succinate dehydrogenase (SDH) and adenylate kinase (AK).

Main Results:

  • Breast cancers with IRG1 deletion showed a worse prognosis, with ~70% being ER-positive.
  • Itaconate selectively inhibited ER-positive breast cancer cell growth by blocking DNA synthesis and inducing apoptosis.
  • IRG1 overexpression decreased intermediates in glycolysis, the TCA cycle, and lipid metabolism, compromising cell biomass and energy.
  • Itaconate inhibited SDH activity, increased ROS, decreased AK activity, and activated AMP-activated protein kinase (AMPK), restoring metabolic homeostasis.

Conclusions:

  • IRG1/Itaconate acts as a regulator of metabolic homeostasis in ER-positive breast cancer cells.
  • This pathway represents a potential therapeutic target for improving breast cancer treatment strategies.
Keywords:
Breast cancerestrogen receptorimmune response gene 1itaconatemetabolic reprogrammingtricarboxylic acid cycle

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