title: Inhibition of SGK1 enhances mAR-induced apoptosis in MCF-7 breast cancer cells.
abstract: Functional membrane androgen receptors (mAR) have previously been described in MCF-7 breast cancer cells. Their stimulation by specific testosterone albumin conjugates (TAC) activate rapidly non-genomic FAK/PI3K/Rac1/Cdc42 signaling, trigger actin reorganization and inhibit cell motility. PI3K stimulates serum and glucocorticoid inducible kinase SGK1, which in turn regulates the function of mAR. In the present study we addressed the role of SGK1 in mAR-induced apoptosis. TAC-stimulated mAR activation elicited apoptosis of MCF-7 cells, an effect significantly potentiated by concomitant incubation of the cells with TAC and the specific SGK1 inhibitors EMD638683 and GSK650394. In line with this, TAC and EMD638683 activated caspase-3. These effects were insensitive to the classical androgen receptor (iAR) antagonist flutamide, pointing to iAR-independent, mAR-induced responses. mAR activation and SGK1 inhibition further considerably augmented the radiation-induced apoptosis of MCF-7 cells. Moreover, TAC- and EMD638683 triggered early actin polymerization in MCF-7 cells. Blocking actin restructuring with cytochalasin B abrogated the TAC- and EMD638683-induced pro-apoptotic responses. Further analysis of the molecular signaling revealed late de-phosphorylation of FAK and Akt. Our results demonstrate that mAR activation triggers pro-apoptotic responses in breast tumor cells, an effect significantly enhanced by SGK1 inhibition, involving actin reorganization and paralleled by down-regulation of FAK/Akt signaling.
authors.affiliation: a Department of Physiology ; University of Tübingen ; Tübingen , Germany.
authors.forename: Guilai
authors.initials: G
authors.lastname: Liu
authors.forename: Sabina
authors.initials: S
authors.lastname: Honisch
authors.forename: Guoxing
authors.initials: G
authors.lastname: Liu
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schmidt
authors.forename: Stavros
authors.initials: S
authors.lastname: Pantelakos
authors.forename: Saad
authors.initials: S
authors.lastname: Alkahtani
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Toulany
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Christos
authors.initials: C
authors.lastname: Stournaras
mesh_terms: D000199:Actins / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors*; D061986:MCF-7 Cells; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000199:Actins; D053148:Caspase 3; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017874:Immediate-Early Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen; D013739:Testosterone; D000099184:Serum-Glucocorticoid Regulated Kinases
keywords: Akt; FAK; Focal Adhesion Kinase (FAK); SGK1; actin; apoptosis; breast cancer; classical androgen receptor (iAR); irradiation; mAR; membrane androgen receptors (mAR); serum and glucocorticoid inducible kinase (SGK1); testosterone albumin conjugates (TAC)