title: 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.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Jilin Province Cancer Hospital, Changchun, Jilin, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Dai
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Mengru
authors.initials: M
authors.lastname: Cao
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ruping
authors.initials: R
authors.lastname: Shao
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Mourad
authors.initials: M
authors.lastname: Majidi
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Ji
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Department of Lymphoma, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Shiyang
authors.initials: S
authors.lastname: Pan
authors.affiliation: Hamon Center for Therapeutic Oncology, The Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: John
authors.initials: J
authors.lastname: Minna
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Reza J
authors.initials: RJ
authors.lastname: Mehran
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Swisher
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Bingliang
authors.initials: B
authors.lastname: Fang
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001310:Auranofin / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000378:metabolism; D040081:Protein Array Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018501:Antirheumatic Agents; D001310:Auranofin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D054481:Thioredoxin Reductase 1; C516124:TXNRD1 protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human
keywords: anticancer agent; biomarkers; drug repurposing; lung cancer