Diet‐derived ergothioneine induces necroptosis in colorectal cancer cells by activating the SIRT3/MLKL pathway

Abstract

Ergothioneine (Egt) is a dietary amino acid which acts as an antioxidant to protect against ageing‐related diseases. We investigated the anti‐cancer properties of Egt in colorectal cancer cells (CRC). Egt treatment exerted cytotoxicity in a dose‐dependent manner, induced reactive oxygen species accumulation, loss of mitochondrial membrane potential and upregulation of the histone deacetylase SIRT3. Immunoblotting analysis indicated that the cell death occurred via necroptosis through activation of the RIP1/RIP3/MLKL pathway. An immunoprecipitation assay unveiled that the interaction between the terminal effector in necroptotic signalling MLKL and SIRT3 increased during the Egt treatment. SIRT3 gene silencing blocked the upregulation of MLKL and abolished the ability of Egt to induce necroptosis. The SIRT3–MLKL interaction may mediate the necroptotic effects of Egt in CRC, suggesting the potential of this dietary amino thione in the prevention of CRC.

Mitochondrial Sirtuins in Chronic Degenerative Diseases: New Metabolic Targets in Colorectal Cancer

“…In vitro studies revealed that the ability of on milk whey to affect HT-29, HCT 116, cell proliferation, cell cycle, apoptosis and metabolism via upregulation of SIRT3 and PPAR along with downregulation of lactate dehydrogenase A (LDHA), SREBP1 and PPARα ( Figure 2 ) [ 119 ]. Intriguingly, another food-derived betaine, ergothioneine, exerts anti-CRC effect through SIRT3 activation [ 120 ]. In vitro ergothioneine treatment can induce cell death via ROS accumulation and necroptotic mixed lineage kinase domain like pseudokinase (MLKL) pathway activation promoting SIRT3 activity and its interaction with MLKL ( Figure 2 ) [ 120 ].…”

“…Intriguingly, another food-derived betaine, ergothioneine, exerts anti-CRC effect through SIRT3 activation [ 120 ]. In vitro ergothioneine treatment can induce cell death via ROS accumulation and necroptotic mixed lineage kinase domain like pseudokinase (MLKL) pathway activation promoting SIRT3 activity and its interaction with MLKL ( Figure 2 ) [ 120 ].…”

“…Nutritional components can intervene in CRC pathogenesis even acting epigenetically. Nutrients acting as epi-nutrients show the ability to activate SIRTs [ 76 , 118 , 119 , 120 ]. Among epi-nutrients , ergothioneine and δ-valerobetaine modulate SIRT3 and SIRT6 and oppose cancer viability and progression [ 76 , 118 , 119 , 120 ].…”

“…Nutrients acting as epi-nutrients show the ability to activate SIRTs [ 76 , 118 , 119 , 120 ]. Among epi-nutrients , ergothioneine and δ-valerobetaine modulate SIRT3 and SIRT6 and oppose cancer viability and progression [ 76 , 118 , 119 , 120 ]. In addition, mangiferin and resveratrol show in vitro anticancer properties in CRC via SIRT/MGF and SIRT1/NF-κB signaling, respectively [ 135 , 150 , 151 ].…”

How Should the Worldwide Knowledge of Traditional Cancer Healing Be Integrated with Herbs and Mushrooms into Modern Molecular Pharmacology?

“…Although there is not enough information about the role of ergothioneine in human physiology, there are strong evidences about its protective properties in our organism [ 447 ]. Ergothioneine mitigated oxaliplatin-induced peripheral neuropathy in rats (Nishida 2018), provoked necroptosis in colorectal cancer cells [ 448 ], and favored adjuvant vaccine cancer immunotherapy by suppressing the function of tumor-associated macrophages [ 449 ]. The blood level of ergothioneine was negatively associated with the risk of cardiometabolic disease and mortality [ 450 ], as well as chronic peripheral neuropathy upon colorectal cancer chemotherapeutic treatment [ 451 ].…”