Oncotarget

Research Papers:

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

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 and Bingliang Fang _

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Oncotarget. 2016; 7:3548-3558. https://doi.org/10.18632/oncotarget.6516

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Abstract

Hongyu Li1,4, Jing Hu1, Shuhong Wu1, Li Wang1, Xiaobo Cao1, Xiaoshan Zhang1, Bingbing Dai1, Mengru Cao1, Ruping Shao1, Ran Zhang1, Mourad Majidi1, Lin Ji1, John V. Heymach2, Michael Wang3, Shiyang Pan5, John Minna6, Reza J. Mehran1, Stephen G. Swisher1, Jack A. Roth1, and Bingliang Fang1

1Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2Department of Thoracic/Head & Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

3Department of Lymphoma, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

4Jilin Province Cancer Hospital, Changchun, Jilin, China

5Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

6Hamon Center for Therapeutic Oncology, The Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA

Correspondence to:

Bingliang Fang, e-mail: bfang@mdanderson.org

Keywords: lung cancer, drug repurposing, anticancer agent, biomarkers

Received: August 19, 2015     Accepted: November 21, 2015     Published: December 09, 2015

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.


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