Methionine enkephalin (MENK) suppresses lung cancer by regulating the Bcl-2/Bax/caspase-3 signaling pathway and enhancing natural killer cell-driven tumor immunity.

The aim of this study was to investigate how methionine enkephalin (MENK) regulates the biological behavior of lung cancer cells and to further explore its anti-lung cancer mechanisms in vitro and in vivo. The results showed that MENK enhanced the expression of opioid receptor (OGFr) and induced apoptosis of lung cancer cells by activating the Bcl-1/Bax/caspase-3 signaling pathway in vitro and in vivo. However, the regulatory effects of MENK disappeared after blockade of the OGFr. This confirmed that a prerequisite for the anti-tumor action of MENK is binding to OGFr. Additionally, we observed that MENK treatment enhanced the immunogenicity of lung cancer by enhancing the exposure of calreticulin and high mobility group box 1, and increasing the expression of NKG2D ligands. Further studies showed that MENK treatment increased the expression of natural killer (NK) cell-related cytokines such as granzyme B and interferon-γ and NK cell activation. Thus, we concluded that MENK might inhibit the proliferation of lung cancer cells by activating the Bcl-2/Bax/caspase-3 signaling pathway and enhancing immunogenicity and NK cell-driven tumor immunity.