Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung cancer cells

Abstract

Auranofin, a gold complex that has been used to treat rheumatoid arthritis in clinics and has documented pharmacokinetic and safety profiles in humans, has recently been investigated for its anticancer activity in leukemia and some solid cancers. However, auranofin's single agent activity in lung cancer is not well characterized. To determine whether auranofin has single agent activity in lung cancer, we evaluated auranofin's activity in a panel of 10 non-small cell lung cancer (NSCLC) cell lines. Cell viability analysis revealed that auranofin induced growth inhibition in a subset of NSCLC cell lines with a half maximal inhibitory concentration (IC50) below 1.0 μM. Treatment with auranofin elicited apoptosis and necroptosis in auranofin-sensitive cell lines. Moreover, the susceptibility of NSCLC cells to auranofin was inversely correlated with TXNRD1 expression in the cells. Transient transfection of the TXNRD1-expressing plasmid in auranofin-sensitive Calu3 cells resulted in partial resistance, indicating that high TXNRD level is one of causal factors for resistance to auranofin. Further mechanistic characterization with proteomic analysis revealed that auranofin inhibits expression and/or phosphorylation of multiple key nodes in the PI3K/AKT/mTOR pathway, including S6, 4EBP1, Rictor, p70S6K, mTOR, TSC2, AKT and GSK3. Ectopic expression of TXNRD1 partially reversed auranofin-mediated PI3K/AKT/mTOR inhibition, suggesting that TXNRD1 may participate in the regulation of PI3K/AKT/mTOR pathway. Administration of auranofin to mice with xenograft tumors derived from NSCLC cells significantly suppressed tumor growth without inducing obvious toxic effects. Our results demonstrated feasibility of repurposing auranofin for treatment of lung cancer.

TUSC2(FUS1)-erlotinib Induced Vulnerabilities in Epidermal Growth Factor Receptor(EGFR) Wildtype Non-small Cell Lung Cancer(NSCLC) Targeted by the Repurposed Drug Auranofin

“…AF inhibits expression and phosphorylation of major effectors of the PI3K/AKT/mTOR pathway1718. In this study, our data support a novel conceptual model in which we identify vulnerabilities in wild type EGFR NSCLC cells following treatment with the TUSC2-erlotinib combination which we found could be targeted with the repurposed drug AF.…”

Activation of endoplasmic reticulum stress promotes autophagy and apoptosis and reverses chemoresistance of human small cell lung cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway

“…The PI3K/AKT/mTOR signaling pathway is a main signaling pathway to regulate cell growth, proliferation, metabolism and survival, commonly deregulated in cancer [30]. Alterations of the PI3K/AKT/mTOR signaling pathway occur at multiple levels, leading to PI3K activation and malignant transformation [31].…”

X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action

“…Trypanothione reductase of L. infantum (Ilari et al, 2012) revealed, albeit at low resolution, evidence for Auranofin’s tetra-acetyl-thio-glucopyranoside moiety binding to the trypanothione binding site, suggesting interference with the substrate as another possible mechanism of inhibition. Dual inhibition of inflammatory and redox pathways by Auranofin makes it a promising candidate for new applications as an anti-cancer agent (Li et al, 2015; Topkas et al, 2015; You and Park, 2015) and in treating of parasitic infections in humans (Debnath et al, 2012a; Madeira et al, 2012; Tejman-Yarden et al, 2013). …”