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.

• Authors: Hongyu Li, Jing Hu, Shuhong Wu, Li Wang, Xiaobo Cao, Xiaoshan Zhang, Bingbing Dai, Mengru Cao, Ruping Shao, Ran Zhang, Mourad Majidi, Lin Ji, John V Heymach, Michael Wang, Shiyang Pan, John Minna, Reza J Mehran, Stephen G Swisher, Jack A Roth, Bingliang Fang
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 3 Pg. 3548-58 (Jan 19 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26657290 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antirheumatic Agents
• Auranofin
• TXNRD1 protein, human
• Thioredoxin Reductase 1
• MTOR protein, human
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• Antirheumatic Agents (pharmacology)
• Apoptosis (drug effects)
• Auranofin (pharmacology)
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (metabolism, pathology, prevention & control)
• Cell Proliferation (drug effects)
• Flow Cytometry
• Humans
• Lung Neoplasms (metabolism, pathology, prevention & control)
• Mice
• Phosphatidylinositol 3-Kinases (chemistry, metabolism)
• Protein Array Analysis
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Thioredoxin Reductase 1 (metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays