Metformin Exerts Anti-Neoplastic Effects via the Reactive Oxygen Species-Dependent Apoptosis and Inhibition of the AMPK/mTOR/Nrf2 Pathway in Papillary Thyroid Cancer

Abstract

Papillary thyroid cancer (PTC) is a tumor associated with a high Nrf2 level. As a first-line antidiabetic medication, Metformin was recently shown antioxidants effects and inhibited nuclear factor erythroid 2-related factor 2 (Nrf2) expression in several malignant cells. However, whether Metformin regulates Nrf2 to inhibit PTC and the mechanism are inconclusive. We aimed to investigate Metformin’s effects on oxidative disorders and its potential molecular mechanisms in PTC. Our results showed that Metformin increased Reactive Oxygen Species (ROS) accumulation in K1 cells. Mechanistically, Metformin significantly promoted ROS generation by inhibiting Nrf2, which induced cellular apoptosis in K1 cells. Moreover, the AMP-Activated Protein Kinases (AMPK)/(the Mammalian target of rapamycin) mTOR signaling partially participates in the apoptosis process. The study showed that Metformin exerted an antitumor activity on K1 cells, via ROS generation and Nrf2 inhibition.