AKT-ing out: SGK kinases come to the fore
| Autor: | Bart Vanhaesebroeck, Larissa S. Moniz |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_treatment
PDK1 phosphoinositide-dependent kinase 1 AKT2 phosphoinositide 3-kinase (PI3K) Biochemistry Targeted therapy PRAS40 proline-rich Akt substrate of 40 kDa FOXO forkhead box O NDRG1 N-Myc downstream-regulated gene 1 qRT-PCR quantitative reverse transcription–PCR protein kinase inhibitor Kinase mammalian target of rapamycin (mTOR) N-Myc downstream-regulated gene 1 (NDRG1) HRP horseradish peroxidase N-Myc neuroblastoma-derived Myc mTORC mTOR complex shRNA short hairpin RNA Female PI3K phosphoinositide 3-kinase Research Article PTEN phosphatase and tensin homologue deleted on chromosome 10 PH pleckstrin homology Breast Neoplasms MTS 3-(4 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium SGK serum- and glucocorticoid-regulated kinase mTOR mammalian target of rapamycin Protein Serine-Threonine Kinases Biology TBST Tris-buffered saline-Tween Immediate early protein Immediate-Early Proteins HEK human embryonic kidney FBS fetal bovine serum GSK3 glycogen synthase kinase 3 medicine Animals Humans Protein Kinase Inhibitors Molecular Biology Protein kinase B GI50 growth inhibition by 50% Cancer Cell Biology medicine.disease signal transduction inhibitor Drug Resistance Neoplasm Cancer cell SGK1 Cancer research Proto-Oncogene Proteins c-akt |
| Zdroj: | Biochemical Journal |
| ISSN: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bj20130617 |
| Popis: | The majority of human cancers harbour mutations promoting activation of the Akt protein kinase, and Akt inhibitors are being evaluated in clinical trials. An important question concerns the understanding of the innate mechanisms that confer resistance of tumour cells to Akt inhibitors. SGK (serum- and glucocorticoid-regulated kinase) is closely related to Akt and controlled by identical upstream regulators {PI3K (phosphoinositide 3-kinase), PDK1 (phosphoinositide-dependent kinase 1) and mTORC2 [mTOR (mammalian target of rapamycin) complex 2]}. Mutations that trigger activation of Akt would also stimulate SGK. Moreover, Akt and SGK possess analogous substrate specificities and are likely to phosphorylate overlapping substrates to promote proliferation. To investigate whether cancers possessing high SGK activity could possess innate resistance to Akt-specific inhibitors (that do not target SGK), we analysed SGK levels and sensitivity of a panel of breast cancer cells towards two distinct Akt inhibitors currently in clinical trials (AZD5363 and MK-2206). This revealed a number of Akt-inhibitor-resistant lines displaying markedly elevated SGK1 that also exhibited significant phosphorylation of the SGK1 substrate NDRG1 [N-Myc (neuroblastoma-derived Myc) downstream-regulated gene 1]. In contrast, most Akt-inhibitor-sensitive cell lines displayed low/undetectable levels of SGK1. Intriguingly, despite low SGK1 levels, several Akt-inhibitor-sensitive cells showed marked NDRG1 phosphorylation that was, unlike in the resistant cells, suppressed by Akt inhibitors. SGK1 knockdown markedly reduced proliferation of Akt-inhibitor-resistant, but not -sensitive, cells. Furthermore, treatment of Akt-inhibitor-resistant cells with an mTOR inhibitor suppressed proliferation and led to inhibition of SGK1. The results of the present study suggest that monitoring SGK1 levels as well as responses of NDRG1 phosphorylation to Akt inhibitor administration could have a use in predicting the sensitivity of tumours to compounds that target Akt. Our findings highlight the therapeutic potential that SGK inhibitors or dual Akt/SGK inhibitors might have for treatment of cancers displaying elevated SGK activity. |
| Databáze: | OpenAIRE |
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