Development of a Small-Molecule Serum- and Glucocorticoid-Regulated Kinase-1 Antagonist and Its Evaluation as a Prostate Cancer Therapeutic

Sherk, Andrea B.; Frigo, Daniel E.; Schnackenberg, Christine G.; Bray, Jeffrey D.; Laping, Nicholas J.; Trizna, Walter; Hammond, Marlys; Patterson, Jaclyn R.; Thompson, Scott K.; Kazmin, Dmitri; Norris, John D.; McDonnell, Donald P.

doi:10.1158/0008-5472.can-08-1047

Cited by 186 publications

(178 citation statements)

References 45 publications

(38 reference statements)

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“…Similar results were observed for two different siRNA oligos against SGK1. These results were confirmed by blocking the function of SGK1 with a SGK1-specific inhibitor, GSK650394 (19), in MEFs (Fig. 6F).…”

Section: Sgk1 Mediates the Inhibitory Effect Of Glucocorticoids On P5supporting

confidence: 53%

Chronic restraint stress attenuates p53 function and promotes tumorigenesis

Feng

Liu²,

Zhang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

171

138

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Epidemiological studies strongly suggest that chronic psychological stress promotes tumorigenesis. However, its direct link in vivo and the underlying mechanisms that cause this remain unclear. This study provides direct evidence that chronic stress promotes tumorigenesis in vivo; chronic restraint, a well-established mouse model to induce chronic stress, greatly promotes ionizing radiation (IR)-induced tumorigenesis in p53 +/− mice. The tumor suppressor protein p53 plays a central role in tumor prevention. Loss or attenuation of p53 function contriubutes greatly to tumorigenesis. We found that chronic restraint decreases the levels and function of p53 in mice, and furthermore, promotes the growth of human xenograft tumors in a largely p53-dependent manner. Our results show that glucocorticoids elevated during chronic restraint mediate the effect of chronic restraint on p53 through the induction of serum-and glucocorticoid-induced protein kinase (SGK1), which in turn increases MDM2 activity and decreases p53 function. Taken together, this study demonstrates that chronic stress promotes tumorigenesis in mice, and the attenuation of p53 function is an important part of the underlying mechanism, which can be mediated by glucocortcoids elevated during chronic restraint.

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Section: Sgk1 Mediates the Inhibitory Effect Of Glucocorticoids On P5supporting

confidence: 53%

Chronic restraint stress attenuates p53 function and promotes tumorigenesis

Feng

Liu²,

Zhang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

171

138

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“…18,31 Our studies suggest that ECMdetached cells with oncogenic Ras mutations could be compromised by SGK-1 inhibition. Indeed, the development of SGK-1 antagonists has already commenced in other cancers, 32,33 and our results suggest that similar inhibitors may be efficacious in eliminating ECM-detached cells with Ras mutations. Interestingly, our findings are also consistent with data suggesting that SGK-1 activity can mediate the sensitivity of cancer cells to targeted therapies.…”

Section: Discussionmentioning

confidence: 53%

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

et al. 2016

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In order for cancer cells to survive during metastasis, they must overcome anoikis, a caspase-dependent cell death process triggered by extracellular matrix (ECM) detachment, and rectify detachment-induced metabolic defects that compromise cell survival. However, the precise signals used by cancer cells to facilitate their survival during metastasis remain poorly understood. We have discovered that oncogenic Ras facilitates the survival of ECM-detached cancer cells by using distinct effector pathways to regulate metabolism and block anoikis. Surprisingly, we find that while Ras-mediated phosphatidylinositol (3)-kinase signaling is critical for rectifying ECM-detachment-induced metabolic deficiencies, the critical downstream effector is serum and glucocorticoid-regulated kinase-1 (SGK-1) rather than Akt. Our data also indicate that oncogenic Ras blocks anoikis by diminishing expression of the phosphatase PHLPP1 (PH Domain and Leucine-Rich Repeat Protein Phosphatase 1), which promotes anoikis through the activation of p38 MAPK. Thus, our study represents a novel paradigm whereby oncogene-initiated signal transduction can promote the survival of ECM-detached cells through divergent downstream effectors. Cell Death and Differentiation (2016) 23, 1271-1282 doi:10.1038/cdd.2016 published online 26 February 2016 Cancer metastasis, the spread of cancer cells to distant parts of the body, accounts for~90% of cancer-related deaths and represents an inherently difficult clinical challenge.1,2 It has become clear that for successful metastasis to occur, cells must overcome a caspase-dependent cell death mechanism, anoikis, which is triggered by detachment from the extracellular matrix (ECM).3 In addition to anoikis evasion, cancer cells must also contend with anoikis-independent cellular alterations that can compromise cellular viability. 4 Chief among these alterations are metabolic deficiencies that are induced by ECM detachment. [5][6][7] These metabolic alterations involve deficiencies in ATP generation, elevated levels of reactive oxygen species, and the induction of autophagy. 6,8,9 Although recent studies have begun to unravel the strategies used by cancer cells to ameliorate metabolic deficiencies during ECM detachment, 10 the signal-transduction cascades responsible for regulating metabolism during ECM detachment in cancer cells remain almost entirely unexplored.The activation of oncogenic signaling pathways is critical to anchorage-independent growth and ultimately to the survival of a variety of distinct cancer cell types during ECM detachment. 4,11 Presumably, this oncogenic signaling is also necessary for resolving the aforementioned ECM-detachment-induced metabolic deficiencies. ErbB2 overexpression in mammary epithelial cells results in a stimulation of phosphatidylinositol (3)-kinase (PI(3)K)/Akt signaling to promote glucose uptake and ATP generation.6 These data raise the question as to how cancer cells that lack ErbB2 overexpression rectify metabolic deficiencies during ECM detachment. Does activation o...

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“…Here we used the small molecule inhibitor for SGK1, GSK650394 (16), to test whether SGK1 is mechanistically involved in the effects of CORT on neurogenesis. As hypothesized, GSK650394 (at 10 nM, 50 nM, and 100 nM) dose-dependently counteracted the CORTinduced reduction in BrdU-positive, proliferating progenitor cells (one-way ANOVA, P = 0.01, F 1,4 = 4.17; Fig.…”

Section: Sgk1mentioning

confidence: 99%

Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis

Anacker

Cattaneo

Musaelyan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

292

215

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Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms mediating these effects are poorly understood. Here we identify the glucocorticoid receptor (GR) target gene, serum-and glucocorticoid-inducible kinase 1 (SGK1), as one such mechanism. Using a human hippocampal progenitor cell line, we found that a small molecule inhibitor for SGK1, GSK650394, counteracted the cortisol-induced reduction in neurogenesis. Moreover, gene expression and pathway analysis showed that inhibition of the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation. Experiments combining the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, demonstrated that SGK1 was involved in the cortisol-induced reduction in progenitor proliferation both downstream of GR, by regulating relevant target genes, and upstream of GR, by increasing GR function. Corroborating the relevance of these findings in clinical and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Our findings identify SGK1 as a mediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression.antidepressants | hypothalamus-pituitary-adrenal axis | stem cells | neuroplasticity

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Development of a Small-Molecule Serum- and Glucocorticoid-Regulated Kinase-1 Antagonist and Its Evaluation as a Prostate Cancer Therapeutic

Cited by 186 publications

References 45 publications

Chronic restraint stress attenuates p53 function and promotes tumorigenesis

Chronic restraint stress attenuates p53 function and promotes tumorigenesis

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis

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