title: Serum and glucocorticoid-regulated kinase 1 (SGK1) activation in breast cancer: requirement for mTORC1 activity associates with ER-alpha expression.
abstract: Mammalian target of rapamycin (mTOR) is an attractive target for cancer treatment. While rapamycin and its derivatives (e.g., everolimus) have been shown to inhibit mTOR signaling and cell proliferation in preclinical models of breast cancer, mTOR inhibition has demonstrated variable clinical efficacy with a trend toward better responses in estrogen receptor alpha positive (ERα+) compared to ERα negative (ERα-) tumors. Recently, serum- and glucocorticoid-regulated kinase 1 (SGK1) was identified as a substrate of mTOR kinase activity. Previous studies have alternatively suggested that either mTORC1 or mTORC2 is exclusively required for SGK1's Ser422 phosphorylation and activation in breast cancer cells. We investigated the effect of rapamycin on the growth of several ERα+ and ERα- breast cancer cell lines and examined differences in the phosphorylation of mTOR substrates (SGK1, p70S6K, and Akt) that might account for the differing sensitivity of these cell lines to rapamycin. We also examined which mTOR complex contributes to SGK1-Ser422 phosphorylation in ERα+ versus ERα- breast cell lines. We then assessed whether inhibiting SGK1 activity added to rapamycin-mediated cell growth inhibition by either using the SGK1 inhibitor GSK650394A or expressing an SGK1 shRNA. We observed sensitivity to rapamycin-mediated growth inhibition and inactivation of insulin-mediated SGK1-Ser422 phosphorylation in ERα+ MCF-7 and T47D cells, but not in ERα- MDA-MB-231 or MCF10A-Myc cells. In addition, either depleting SGK1 with shRNA or inhibiting SGK1 with GSK650394A preferentially sensitized MDA-MB-231 cells to rapamycin. Finally, we found that rapamycin-sensitive SGK1-Ser422 phosphorylation required ERα expression in MCF-7 derived cell lines. Therefore, targeting SGK1 activity may improve the efficacy of rapamycin and its analogs in the treatment of ERα- breast cancer.
authors: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. bhall@bsd.uchicago.edu
authors: Ben A
authors: BA
authors: Hall
authors: Tae Yeon
authors: TY
authors: Kim
authors: Maxwell N
authors: MN
authors: Skor
authors: Suzanne D
authors: SD
authors: Conzen
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005663:Furans / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology / Q000502:physiology; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D018931:Antineoplastic Agents, Hormonal; D003907:Dexamethasone; D020536:Enzyme Activators; D047628:Estrogen Receptor alpha; D005663:Furans; D017874:Immediate-Early Proteins; D007328:Insulin; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011725:Pyridines; D011743:Pyrimidines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D019284:Thapsigargin; D000099184:Serum-Glucocorticoid Regulated Kinases; C506487:ESR1 protein, human; C522973:PI103