Anti-inflammatory and metabolic reprogramming effects of MENK produce antitumor response in CT26 tumor-bearing mice

Abstract

Methionine enkephalin (MENK), an endogenous opioid peptide, has a role in nervous system, immune system, and anticancer therapy. Inflammation, metabolism and cancer are closely intertwined with each other. This study is to identify the correlation of the antitumor effects of MENK with systemic inflammation, liver metabolism, and immune cells as myeloid‐derived suppressor cells (MDSCs). We established a subcutaneous CT26 colon carcinoma model and a cyclophosphamide‐induced immunosuppressive model subjected to MENK. AML12 and MDSCs were used as in vitro models. The results showed that MENK treatment degraded tumor growth and inhibited proinflammatory cytokines both in tumor tissues and serum. The MENK‐treated tumor mice showed normalized liver function with glycolipid metabolic homeostasis. No inhibitory effect on CT26 tumor cell in vitro, but only reduced lipid synthesis in AML12 were presented by MENK. Meanwhile, MENK invigorated immune response in both two animal models by markedly suppressing MDSCs and enhancing T cells response. In vitro MENK‐treated MDSCs showed reduced glycolysis and less ROS production, which was mediated by PI3K/AKT/mTOR pathway. Opioid receptor antagonist naltrexone reversed most of the regulation. These results illustrate that MENK preventing development of colon carcinoma might be correlated with the suppression of inflammation, improving metabolism in liver as well as in MDSCs partly through opioid receptor, which brings new elements supporting the adjuvant therapy for tumor by MENK.

Novel therapeutic strategies targeting myeloid-derived suppressor cell immunosuppressive mechanisms for cancer treatment

“…Other upstream pathways of MDSC ROS expression may include the opioid signalling pathway. Treatment with the endogenous opioid peptide methionine enkephalin (MENK) reduced CT26 CRC tumour growth in vivo , and in vitro incubation of MDSCs with MENK led to reduced glycolysis and ROS production, indicating that opioid pathways may have anti-tumoural properties [ 86 ]. Tumour cell-derived granulocyte macrophage-colony stimulating factor (GM-CSF) activates MDSCs via inducing STAT3-mediated fatty acid transport protein 2 (FATP2), and pharmacological blockade of the latter via lipofermata reduced ROS expression, MDSC immunosuppressive activity, and tumour burden [ 87 ].…”

Multi-faced roles of reactive oxygen species in anti-tumor T cell immune responses and combination immunotherapy

“…Methionine enkephalin, an opioid receptor agonist, acts as a significant mediator to connect the nervous system and the immune system [123]. In a murine model of CT26 colon carcinoma, methionine enkephalin reduces glycolysis and decreases ROS production in MDSCs, which promotes the MDSCs differentiation and increases CD8 + T cells infiltration in the lymphoid organs and tumor tissue, resulting in the enhanced immune responses in both tumor-bearing mice and cytoxan-induced immunosuppressive mice, and ultimately, inhibiting the tumor progression [124]. As 4 S 4 is a mineral medicine usually used as one component of some formulations in the treatment of hematological malignancies [125].…”

A “Drug-Dependent” Immune System Can Compromise Protection against Infection: The Relationships between Psychostimulants and HIV

“…The upregulation of MHC class II expression and that of key co-stimulatory molecules on these antigen-presenting cells was also observed following met-enkephalin treatment [ 150 , 151 ]. Met-enkephalin was seen to have antitumor effects by balancing the immune response suppressing myeloid-derived suppressor cells and enhancing T-cells through a mechanism blocked by naltrexone [ 152 ]. These antitumor effects might correlate with the suppression of inflammation, further evidence supporting the use of met-enkephalin in adjuvant therapy for tumors.…”