Hemin Prevents Increased Glycolysis in Macrophages upon Activation: Protection by Microbiota-Derived Metabolites of Polyphenols.

Catalina Carrasco-Pozo,Kah Ni Tan,Vicky M Avery

doi:10.3390/antiox9111109

Catalina Carrasco-Pozo, Kah Ni Tan + Show 1 more

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https://doi.org/10.3390/antiox9111109

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Journal: Antioxidants	Publication Date: Nov 11, 2020
Citations: 10	License type: CC BY 4.0

Affiliation: Griffith University

Abstract

Meat consumption plays a critical role in the development of several types of cancer. Hemin, a metabolite of myoglobin produced after meat intake, has been demonstrated to be involved in the cancer initiation phase. Macrophages are key components of the innate immunity, which, upon activation, can prevent cancer development by eliminating neoplastic cells. Metabolic reprogramming, characterized by high glycolysis and low oxidative phosphorylation, is critical for macrophage activation. 3,4-dihydroxyphenylacetic acid (3,4DHPAA) and 4-hydroxyphenylacetic acid (4HPAA), both microbiota-derived metabolites of flavonoids, have not been extensively studied although they exert antioxidant properties. The aim of this study was to determine the effect of hemin on the anticancer properties of macrophages and the role of 3,4DHPAA and 4HPAA in metabolic reprogramming and activation of macrophages leading to the elimination of cancer cells. The results showed that hemin inhibited glycolysis, glycolytic, and pentose phosphate pathway (PPP) enzyme activities and hypoxia-inducible factor-1 alpha (HIF-1α) stabilization, which interferes with macrophage activation (evidenced by decreased interferon-γ-inducible protein 10 (IP-10) release) and their ability to eliminate cancer cells (via cytotoxic mediators and phagocytosis). Hemin also reduced the mitochondrial membrane potential (MMP) and mitochondrial mass in macrophages. 3,4DHPAA and 4HPAA, by stimulating glycolysis and PPP, prevented the impairment of the macrophage anticancer activity induced by hemin. In conclusion, 3,4HPAA and 4HPAA administration could represent a promising strategy for preventing the reduction of macrophage activation induced by hemin.

Highlights

According to the latest data provided by the World Health Organization, cancer is the second leading cause of death globally, and is responsible for an estimated 9.6 million deaths in 2018 [1]
Our results showed that LPS and IFNγ, as well as the metabolites, 3,4DHPAA and 4-hydroxyphenylacetic acid (4HPAA), increased glycolysis (Figures 3A and 8A,B), and the activities of the glycolytic and phosphate pathway (PPP) enzymes (Figure 3B,D and Figure 9A–F), which is in line with the metabolic adaptations that macrophages undergo upon activation towards proinflammatory and anticancer phenotypes [58,59,60]
Hemin decreased HIF-1α stabilization induced by proinflammatory signals and the metabolites (Figure 4A,B, Figure 10A–D). These findings suggest that 3,4DHPAA and 4HPAA, by preventing hemin-induced destabilization of HIF-1α, promote the expression of glycolytic enzymes, which could contribute to the increase in glycolysis and macrophage activation

Summary

Introduction

According to the latest data provided by the World Health Organization, cancer is the second leading cause of death globally, and is responsible for an estimated 9.6 million deaths in 2018 [1]. About one in six deaths are due to cancer [2]. Macrophages are innate immune cells that have a pivotal role in cancer prevention, as upon activation, they can identify emerging cancer cells and eliminate them [3]. Macrophages kill cancer cells through phagocytosis and the production of cytotoxic soluble factors, such as cytokines and chemokines [4,5]. Metabolic reprogramming, characterized by high glycolysis and low oxidative phosphorylation (OXPHOS), is critical for macrophage activation towards the M1 phenotype that is characterized by proinflammatory and anticancer properties [6].

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