title: Metformin suppresses growth of human head and neck squamous cell carcinoma via global inhibition of protein translation.
abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer in the world; the main risk factors are alcohol and tobacco use. Advancements in therapies have yet to improve the prognosis of HNSCC. The connection between diabetes and cancer is being recognized, and metformin has been shown to decrease cancer incidence in diabetic patients. Accordingly, here, for the first time, we investigated metformin's efficacy on the growth and viability of human HNSCC FaDU and Detroit cells. Our results show that metformin treatment (5-20 mM) dose-dependently inhibits the growth of both cell lines. In FaDU cells, metformin caused 18-57% and 35-81% growth inhibition after 48 and 72 h treatments, respectively. Similarly, in Detroit 562 cells, 48 and 72 h metformin treatment resulted in 20-57% and 33-82% inhibition, respectively. Mechanistically, metformin caused G 1 arrest, which coincided with a decrease in the protein levels of CDKs (2, 4 and 6), cyclins (D1 and E) and CDK inhibitors (p15, p16, p18 and p27), but no change in p19 and p21. Metformin also decreased the levels of oncogenic proteins Skp2 and β-Trcp. In other studies, metformin decreased the phosphorylation of 4E-BP1 at Ser65, Thr37/46 and Thr70 sites, but drastically increased the phosphorylation of EF2 at Thr56 and AMPK at Thr172, which results in global translational inhibition. In summary, the observed wide spectrum of mechanistic effects of metformin on HNSCC cells provides support for the anticancer capability of the drug and its potential use in future therapies.
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver, CO, USA.
authors.forename: Arron
authors.initials: A
authors.lastname: Sikka
authors.forename: Manjinder
authors.initials: M
authors.lastname: Kaur
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.forename: Gagan
authors.initials: G
authors.lastname: Deep
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000032:analysis / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: C471644:BTRC protein, human; C000614131:CDKN2A protein, human; D019927:Cyclin E; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D009363:Neoplasm Proteins; D044786:S-Phase Kinase-Associated Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008687:Metformin; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D020741:rho GTP-Binding Proteins