The DOI matches its Crossref record; 39 of the 41 references it cites were found in a registry or an index.
Development of a Small-Molecule Serum- and Glucocorticoid-Regulated Kinase-1 Antagonist and Its Evaluation as a Prostate Cancer Therapeutic
Open accessPublished version of a preprint
Abstract
Androgens, through their actions on the androgen receptor (AR), are required for the development of the prostate and contribute to the pathologic growth dysregulation observed in prostate cancers. Consequently, androgen ablation has become an essential component of the pharmacotherapy of prostate cancer. In this study, we explored the utility of targeting processes downstream of AR as an alternate approach for therapy. Specifically, we show that the serum and glucocorticoid-regulated kinase 1 (SGK1) gene is an androgen-regulated target gene in cellular models of prostate cancer. Furthermore, functional serum- and glucocorticoid-regulated kinase 1 (SGK1) protein, as determined by the phosphorylation of its target Nedd4-2, was also increased with androgen treatment. Importantly, we determined that RNA interference–mediated knockdown of SGK1 expression attenuates the androgen-mediated growth of the prostate cancer cell line LNCaP. Given these findings, we explored the utility of SGK1 as a therapeutic target in prostate cancer by developing and evaluating a small-molecule inhibitor of this enzyme. From these studies emerged GSK650394, a competitive inhibitor that quantitatively blocks the effect of androgens on LNCaP cell growth. Thus, in addition to androgen ablation, inhibition of pathways downstream of AR is likely to have therapeutic utility in prostate cancer. [Cancer Res 2008;68(18):7475–83]
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“We treated the 6 lines of cortical neurons with two different SGK1 inhibitors, GSK650394 (GSK, 100 nM) [26] or EMD638683 (6 µM) [27] for 72 h and found marked reduction in the immunostaining of AT8 or S214 phospho-specific antibodies (Figs. 3a–c, S4, S5).”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [26]
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1 retracted
Sun, M., Yang, L., Feldman, R. I., Sun, X.-M., Bhalla, K. N., Jove, R., Nicosia, S. V., & Cheng, J. Q. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306295200 · Cited by 175
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“Specifically, upon PI3K activation, SGK1 is phosphorylated at Ser 422 by an as yet unidentified kinase, referred to as the phosphoinositide-dependent protein kinase (PDK)-2, followed by the phosphorylation of Thr 256 within the activation loop of the SGK1 catalytic domain by PDK1 to become fully activated (19).”
InfluentialBolla, M., Collette, L., Blank, L., Warde, P., Dubois, J. B., Mirimanoff, R.-O., Storme, G., Bernier, J., Kuten, A., Sternberg, C., et al. (2002) · The Lancet · doi:10.1016/s0140-6736(02)09408-4 · Cited by 1,686 · cited 1×
“Although 80% of patients with local or metastatic prostate cancer initially respond favorably to androgen ablation therapy, most patients eventually experience a relapse of the disease, which is then considered to be hormone refractory (2, 3).”
Molecular Mechanisms of Human Hypertension
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“lacking the sgk1 gene have higher sodium excretion and lower blood pressure than wild-type mice when fed a low-sodium diet (33, 34).”
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“Specifically, upon PI3K activation, SGK1 is phosphorylated at Ser(422) by an as yet unidentified kinase, referred to as the phosphoinositide-dependent protein kinase (PDK)-2, followed by the phosphorylation of Thr(256) within the activation loop of the SGK1 catalytic domain by PDK1 to become fully activated (19).”
Park, J., Leong, M., Buse, P., Maiyar, A. C., Firestone, G. L., & Hemmings, B. (1999) · EMBO Journal · doi:10.1093/emboj/18.11.3024 · Cited by 588
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“Whereas SGK1 and SGK3 have been shown to phosphorylate many of the same target proteins in vitro , differences in subcellular localization suggest that these proteins regulate distinct signaling pathways (36).”
Lawton, C., Winter, K., Murray, K., Machtay, M., Mesic, J., Hanks, G., Coughlin, C. T., & Pilepich, M. (2001) · International Journal of Radiation Oncology, Biology, Physics · doi:10.1016/s0360-3016(00)01516-9 · Cited by 386 · cited 1×
“Although 80% of patients with local or metastatic prostate cancer initially respond favorably to androgen ablation therapy, most patients eventually experience a relapse of the disease, which is then considered to be hormone refractory (2, 3).”
The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB
Biondi, R. M., Kieloch, A., Currie, R. A., Deak, M., & Alessi, D. R. (2001) · The EMBO Journal · doi:10.1093/emboj/20.16.4380 · Cited by 377
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Akt-regulated pathways in prostate cancer
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“This is reflected by the high incidence of lossof-function mutations in the gene that encodes the PI3K negative regulator phosphatase and tensin homologue (PTEN) in prostate cancers (21, 22).”
PTEN: from pathology to biology
Sulis, M. L. (2003) · Trends in Cell Biology · doi:10.1016/s0962-8924(03)00175-2 · Cited by 342 · cited 1×
“This is reflected by the high incidence of lossof-function mutations in the gene that encodes the PI3K negative regulator phosphatase and tensin homologue (PTEN) in prostate cancers (21, 22).”
Wu, W., Chaudhuri, S., Brickley, D. R., Pang, D., Karrison, T. G., & Conzen, S. D. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-2546 · Cited by 317
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“Active mTOR contributes to an enhancement of the translation rates of various proteins involved in cell cycle progression, including cyclins D1 and D2 (7).”
InfluentialInsulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase
Avruch, J., Hara, K., Lin, Y., Liu, M., Long, X., Ortiz-Vega, S., & Yonezawa, K. (2006) · Oncogene · doi:10.1038/sj.onc.1209882 · Cited by 301 · cited 1×
“In addition, Xu and colleagues indicated that SGK1 may activate mTOR through the activation of various cellular transporters and the subsequent influx of certain nutrients and amino acids (7, 35).”
Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: The MPAKT model
Majumder, P. K., Yeh, J. J., George, D. J., Febbo, P. G., Kum, J. B., Xue, Q., Bikoff, R., Ma, H., Kantoff, P. W., Golub, T. R., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1232229100 · Cited by 283 · cited 1×
“Transgenic mice expressing a prostate-restricted, constitutively active Akt develop prostate intraepithelial neoplasia but never develop prostate cancer (38).”
Frödin, M., Antal, T. L., Dümmler, B. A., Jensen, C. J., Deak, M., Gammeltoft, S., & Biondi, R. M. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf551 · Cited by 275
Leong, M., Maiyar, A. C., Kim, B., O'Keeffe, B. A., & Firestone, G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211649200 · Cited by 254 · cited 1×
“This is notable considering that others have shown that SGK1 expression, in response to various stimuli, is typically rapid and transient (12).”
Ma, X.-Q., der Made, A. C. J. Z.-V., Autar, B., van der Korput, H. A., Vermeij, M., van Duijn, P. V., Cleutjens, K., de Krijger, R. D., Krimpenfort, P., Berns, A., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4519 · Cited by 204 · cited 1×
“In fact, the prostate-specific PTEN knockout mice develop invasive prostate cancer with 100% penetrance, indicating that within the context of the murine prostate, constitutive PI3K signaling is sufficient for the development of cancer (23).”
In vivo role of the PIF‐binding docking site of PDK1 defined by knock‐in mutation
Collins, B. J., Deak, M., Arthur, J. S. C., Armit, L. J., & Alessi, D. R. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg407 · Cited by 183
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“Although activation of Akt by androgens via a nongenomic mechanism has been described, this phenomenon has never been reported to occur in LNCaP cells, which exhibit constitutive PI3K and Akt activation due to their PTEN-null status (31, 39, 40).”
Bell, L. M., Leong, M., Kim, B., Wang, E., Park, J., Hemmings, B., & Firestone, G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002076200 · Cited by 164
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“Additionally, SGK1 may regulate mTOR activity in a more direct manner through the phosphorylation and inactivation of TSC2, a negative regulator of mTOR, because the expression of constitutively active SGK1 in cardiomyocytes is associated with an enhancement of TSC2 phosphorylation and mTOR activity (24).”
Serum- and Glucocorticoid-Regulated Kinase (SGK1) Gene and Blood Pressure
Busjahn, A., Aydın, A., Uhlmann, R., Krasko, C., Bähring, S., Szelestei, T., Feng, Y., Dahm, S., Sharma, A. M., Luft, F. C., et al. (2002) · Hypertension · doi:10.1161/01.hyp.0000030153.19366.26 · Cited by 127 · cited 1×
“lacking the sgk1 gene have higher sodium excretion and lower blood pressure than wild-type mice when fed a low-sodium diet (33, 34).”
Imaizumi, K., Tsuda, M., Wanaka, A., Tohyama, M., & Takagi, T. (1994) · Molecular Brain Research · doi:10.1016/0169-328x(94)90090-6 · Cited by 122
Xu, J., Liu, D., Gill, G. N., & Zhou, S.-Y. (2001) · Journal of Cell Biology · doi:10.1083/jcb.200105089 · Cited by 120 · cited 1×
“SGK3 is localized to endosomes where it has been suggested to play a role in endocytosis (37), unlike the defined role in growth and survival ascribed to SGK1.”
Maiyar, A. C., Phu, P. T., Huang, A. J. Y., & Firestone, G. L. (1997) · Molecular Endocrinology · doi:10.1210/mend.11.3.9893 · Cited by 104
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“One of the most well-characterized roles for SGK1 is in hypertension where SGK1 phosphorylates and inhibits the ubiquitin ligase neural precursor cell–expressed, developmentally down-regulated protein 4-2 (Nedd4-2) at Ser(468) (S468), which ultimately affects epithelial sodium ion transport (32).”
Transcriptional regulation of prostate kallikrein-like genes by androgen
Wolf, D. A., Schulz, P. J., & Fittler, F. (1992) · Molecular Endocrinology · doi:10.1210/mend.6.5.1376410 · Cited by 98
Sgk1, a cell survival response in neurodegenerative diseases
Schoenebeck, B., Bader, V., Zhu, X., Schmitz, B., Lübbert, H., & Stichel, C. C. (2005) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2005.07.017 · Cited by 82
Kazmin, D., Prytkova, T., Cook, C., Wolfinger, R., Chu, T.-M., Beratan, D., Norris, J., Chang, C.-Y., & McDonnell, D. (2006) · Molecular Endocrinology · doi:10.1210/me.2005-0309 · Cited by 72 · cited 1×
“Microarray analyses done in our laboratory revealed that the SGK1 gene is regulated by androgens in the LNCaP prostate cancer cell line (5).”
Self-citationSerum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival
Shanmugam, I., Cheng, G., Terranova, P. F., Thrasher, J. B., Thomas, C. P., & Li, B. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402227 · Cited by 63 · cited 1×
“It has been suggested that SGK1 may regulate AR transcriptional activity, affecting androgen-mediated prostate cancer growth through a positive feedback mechanism (6).”
Regulation of sodium transport in M-1 cells.
Nakhoul, N., Hering-Smith, K., Gambala, C., & Hamm, L. (1998) · AJP - Renal Physiology · doi:10.1152/ajprenal.1998.275.6.f998 · Cited by 46 · cited 1×
“in M-1 cells as previously reported (30).”
Differential effects of prostate cancer therapeutics on neuroendocrine transdifferentiation
Frigo, D. E., & McDonnell, D. P. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-0480 · Cited by 41 · cited 2×
“Western blots were done as previously described (28).”
Self-citationHollister, R., Page, K. J., & Hyman, B. (1997) · Neuroscience · doi:10.1016/s0306-4522(97)00014-6 · Cited by 41
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The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis
Massie, C. E., Lynch, A., Ramos‐Montoya, A., Boren, J., Stark, R., Fazli, L., Warren, A., Scott, H., Madhu, B., Sharma, N., et al. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.158 · Cited by 624
“…prostate cancer (e.g., WWP1, ERBB2, MEK5, SGK1 and IGF1R) (Figure 2C; Craft et al, 1999; Hellawell et al, 2002; Mehta et al, 2003; Chen et al, 2007; Sherk et al, 2008), the combined analysis of direct AR targets and androgen-regulated genes also revealed a significant enrichment of metabolic…”
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“Some pieces of evidence suggest that various ATP-competitive inhibitors lack selectivity for all SGK isoforms, as they share similar affinity for different isoforms [87, 88].”
Background
Metadata
- Authors
- Sherk, A. B., Frigo, D. E., Schnackenberg, C. G., Bray, J. D., Laping, N. J., Trizna, W., Hammond, M., Patterson, J. R., Thompson, S. K., Kazmin, D., Norris, J. D., & McDonnell, D. P.
- Affiliations
- Duke Medical Center (US)
- Houston Methodist (US)
- GlaxoSmithKline (United States) (US)
- Venue
- Cancer Research
- Published
- 2008-09-14
- Volume
- 68
- Issue
- 18
- Pages
- 7475-7483
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2562281
- OpenAlex
- W2127577957
- Cited by
- 211
- References
- 41
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 7 · 2023: 12 · 2022: 19 · 2021: 20 · 2020: 17 · 2019: 10 · 2018: 12 · 2017: 12 · 2016: 13 · 2015: 12 · 2014: 14 · 2013: 8 · 2012: 9
- FWCI
- 8.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense
- GlaxoSmithKline
- University of Dundee
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK072794, R01DK065251)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Medicine › Urology › Urinary Bladder and Prostate Research
- Keywords
- SGK1, prostate cancer, androgen receptor, androgen signaling, Nedd4-2, small-molecule kinase inhibitors, LNCaP cells, androgen deprivation therapy
- MeSH terms
- Serum-Glucocorticoid Regulated Kinases, Benzoates, HeLa Cells, Humans, Male, Prostatic Neoplasms, Receptors, Androgen, RNA, Messenger, Metribolone, Up-Regulation, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Bridged Bicyclo Compounds, Heterocyclic, RNA, Small Interfering, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Growth Processes
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