NFE2L2 and neoplasm: Interestingly, melatonin seems to influence the Nrf-2 signaling pathway in a pleiotropic manner, where it activates the Nrf-2 pathway via melatonin receptors (MT1 and MT2) and SIRT1 and PI3K/AKT pathways in non-tumorigenic cells, and also inhibits the SGK1-mediated upregulation of Nrf-2 in tumor cells [217].