title: A dihydroselenoquinazoline inhibits S6 ribosomal protein signalling, induces apoptosis and inhibits autophagy in MCF-7 cells.
abstract: The PI3K/Akt/mTOR/S6 ribosomal protein signalling pathway is a key potential target in breast cancer therapy, playing a central role in proliferation and cell survival. In this study, we found that the seleno-compound 2,4-dihydroselenoquinazoline (3a) generally inhibited this signalling axis in MCF-7 breast cancer cells and caused downregulation of S6 ribosomal protein phosphorylation in a dose- and time-dependent manner. Furthermore, 3a caused a dose- and time-dependent decrease in MCF-7 cell viability as well as cell cycle arrest in G2/M. Interestingly 3a also induced apoptosis, as evidenced by cleavage of PARP and caspase-7, and inhibited autophagy, as demonstrated by accumulation of LC3-II and p62/SQSTM1. Given that induction of autophagy has been previously described as a mechanism by which some breast cancer cells counteract proapoptotic signalling and develop resistance to anti-hormone therapy, this suggests that this derivative, which both triggers apoptosis and inhibits autophagy, may be beneficial in preventing and overcoming resistance in breast cancer cells. The data also show the complexity of this signalling axis which is far from being understood.
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain; Instituto de Salud Tropical, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, Scotland, UK.
authors.forename: Dahlia
authors.initials: D
authors.lastname: Doughty-Shenton
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Plano
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Font
authors.affiliation: Departamento de Ciencias de la Salud, Universidad Pública de Navarra, Avda. Barañáin s/n, E-31008 Pamplona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Encío
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain. Electronic address: jpalop@unav.es.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Palop
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sanmartín
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D038601:Ribosomal Protein S6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C000598339:2,4-dihydroselenoquinazoline; D016566:Organoselenium Compounds; D011799:Quinazolines; D038601:Ribosomal Protein S6
keywords: Apoptosis; Autophagy; Cell cycle arrest; Quinazoline; S6 ribosomal protein; Selenium