In Preclinical Model of Ovarian Cancer, the SGK1 Inhibitor SI113 Counteracts the Development of Paclitaxel Resistance and Restores Drug Sensitivity

D’Antona, Lucia; Dattilo, Vincenzo; Catalogna, Giada; Scumaci, Domenica; Fiumara, Claudia Vincenza; Musumeci, Francesca; Perrotti, Giuseppe; Schenone, Silvia; Tallerico, Rossana; Spoleti, Cristina Barbara; Costa, Nicola; Iuliano, Rodolfo; Cuda, Giovanni; Amato, Rosario; Perrotti, Nicola

doi:10.1016/j.tranon.2019.05.008

Cited by 27 publications

(17 citation statements)

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“…The activation of CCR2 is involved in resistance to regorafenib, a multikinase inhibitor, and cabazitaxel in colon and prostate cancer cells [ 33 , 34 ]. SGK1 is associated with Akt and phosphoinositide 3-kinase inhibitor and paclitaxel resistance in breast and ovarian cancer cells [ 51 , 52 , 53 ]. Additionally, SGK1, CCR2, and SGK1 mRNA and protein expression, and the activation of SGK1 and FGFR1, were higher in KMS-20 cells than in KMS-26 and KMS-28BM cells.…”

Section: Discussionmentioning

confidence: 99%

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells

et al. 2021

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Multiple myeloma (MM) is an incurable malignancy often associated with primary and acquired resistance to therapeutic agents, such as proteasome inhibitors. However, the mechanisms underlying the proteasome inhibitor resistance are poorly understood. Here, we elucidate the mechanism of primary resistance to bortezomib and ixazomib in the MM cell lines, KMS-20, KMS-26, and KMS-28BM. We find that low bortezomib and ixazomib concentrations induce cell death in KMS-26 and KMS-28BM cells. However, high bortezomib and ixazomib concentrations induce cell death only in KMS-20 cells. During Gene Expression Omnibus analysis, KMS-20 cells exhibit high levels of expression of various genes, including anti-phospho-fibroblast growth factor receptor 1 (FGFR1), chemokine receptor type (CCR2), and serum and glucocorticoid regulated kinase (SGK)1. The SGK1 inhibitor enhances the cytotoxic effects of bortezomib and ixazomib; however, FGFR1 and CCR2 inhibitors do not show such effect in KMS-20 cells. Moreover, SGK1 activation induces the phosphorylation of NF-κB p65, and an NF-κB inhibitor enhances the sensitivity of KMS-20 cells to bortezomib and ixazomib. Additionally, high levels of expression of SGK1 and NF-κB p65 is associated with a low sensitivity to bortezomib and a poor prognosis in MM patients. These results indicate that the activation of the SGK1/NF-κB pathway correlates with a low sensitivity to bortezomib and ixazomib, and a combination of bortezomib and ixazomib with an SGK1 or NF-κB inhibitor may be involved in the treatment of MM via activation of the SGK1/NF-κB pathway.

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Section: Discussionmentioning

confidence: 99%

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells

et al. 2021

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“…In ovarian carcinoma, in vitro assays showed that in glucocorticoid receptor (GR)-positive HeyA8 and SKOV3 cells, dexamethasone (100 nM) treatment upregulated the pro-survival genes SGK1, and MKP1/DUSP1 and inhibited carboplatin/gemcitabine-induced cell death ( 93 ). However, in a preclinical model of ovarian cancer, the SGK1 inhibitor SI113 counteracted the development of paclitaxel resistance and restored drug sensitivity ( 94 ).…”

Section: Functional Roles Of Sgk1 In Cancermentioning

confidence: 99%

“…Subsequent studies have shown that SI113 induced cell death, thus counteracting cell proliferation in various cancer cell lines ( 30 , 67 ). Specifically, SI113 induced cell apoptosis, both alone and synergistically with paclitaxel in RKO cells ( 67 ) and ovarian cancer cells ( 94 ), or synergized with radiotherapy in hepatocarcinoma models in vitro and in vivo ( 68 ). Remarkably, multiple studies have confirmed that SI113 exhibits powerful anti-tumor effects in glioblastoma multiforme, including activating cell apoptosis, induction of endoplasmic reticulum stress, inhibition of epithelial-to-mesenchymal transition, and especially stimulation of cytotoxic autophagy ( 63 , 64 , 69 , 71 , 147 ).…”

Section: Sgk1 Inhibitorsmentioning

confidence: 99%

SGK1 in Human Cancer: Emerging Roles and Mechanisms

et al. 2021

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Serum and glucocorticoid-induced protein kinase 1 (SGK1) is a member of the “AGC” subfamily of protein kinases, which shares structural and functional similarities with the AKT family of kinases and displays serine/threonine kinase activity. Aberrant expression of SGK1 has profound cellular consequences and is closely correlated with human cancer. SGK1 is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in the genesis and development of many human cancers. Abnormal expression of SGK1 has been found in tissue and may hopefully become a useful indicator of cancer progression. In addition, SGK1 acts as a prognostic factor for cancer patient survival. This review systematically summarizes and discusses the role of SGK1 as a diagnostic and prognostic biomarker of diverse cancer types; focuses on its essential roles and functions in tumorigenesis, cancer cell proliferation, apoptosis, invasion, metastasis, autophagy, metabolism, and therapy resistance and in the tumor microenvironment; and finally summarizes the current understanding of the regulatory mechanisms of SGK1 at the molecular level. Taken together, this evidence highlights the crucial role of SGK1 in tumorigenesis and cancer progression, revealing why it has emerged as a potential target for cancer therapy.

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“…It has recently been demonstrated that SGK1 is a crucial step in mediating cell survival, proliferation, and differentiation via phosphorylation of Mouse Double Minutes 2 (MDM2), which controls p53 ubiquitylation and proteasomal degradation (Amato et al, 2009). SGK1 also influences mitotic stability by affecting the expression of RANBP1 (Ran-specific binding protein 1), the pivotal regulator of GTPase RAN (Amato et al, 2013;D'Antona et al, 2019). More recently, it has been shown that SGK1 through RANBP1/RAN strictly regulates the nucleocytoplasmic transport of pre-miRNAs, a necessary condition for miRNAs maturation, thus modulating the epigenomic framework of the cell (Dattilo et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

The Emerging Role of SGK1 (Serum- and Glucocorticoid-Regulated Kinase 1) in Major Depressive Disorder: Hypothesis and Mechanisms

et al. 2020

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Major depressive disorder (MDD) is a heterogeneous psychiatric disease characterized by persistent low mood, diminished interests, and impaired cognitive and social functions. The multifactorial etiology of MDD is still largely unknown because of the complex genetic and environmental interactions involved. Therefore, no established mechanism can explain all the aspects of the disease. In this light, an extensive research about the pathophysiology of MDD has been carried out. Several pathogenic hypotheses, such as monoamines deficiency and neurobiological alterations in the stress-responsive system, including the hypothalamic-pituitary-adrenal (HPA) axis and the immune system, have been proposed for MDD. Over time, remarkable studies, mainly on preclinical rodent models, linked the serum-and glucocorticoid-regulated kinase 1 (SGK1) to the main features of MDD. SGK1 is a serine/threonine kinase belonging to the AGK Kinase family. SGK1 is ubiquitously expressed, which plays a pivotal role in the hormonal regulation of several ion channels, carriers, pumps, and transcription factors or regulators. SGK1 expression is modulated by cell stress and hormones, including gluco-and mineralocorticoids. Compelling evidence suggests that increased SGK1 expression or function is related to the pathogenic stress hypothesis of major depression. Therefore, the first part of the present review highlights the putative role of SGK1 as a critical mediator in the dysregulation of the HPA axis, observed under chronic stress conditions, and its controversial role in the neuroinflammation as well. The second part depicts the negative regulation exerted by SGK1 in the expression of both the brain-derived neurotrophic factor (BDNF) and the vascular endothelial growth factor (VEGF), resulting in an anti-neurogenic activity. Finally, the review focuses on the antidepressant-like effects of anti-oxidative nutraceuticals in several preclinical model of depression, resulting from the restoration of the physiological expression and/or activity of SGK1, which leads to an increase in neurogenesis. In summary, the purpose of this review is a systematic analysis of literature depicting SGK1 as molecular junction of the complex mechanisms underlying the MDD in an effort to suggest the kinase as a potential biomarker and strategic target in modern molecular antidepressant therapy.

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In Preclinical Model of Ovarian Cancer, the SGK1 Inhibitor SI113 Counteracts the Development of Paclitaxel Resistance and Restores Drug Sensitivity

Cited by 27 publications

References 61 publications

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells

SGK1 in Human Cancer: Emerging Roles and Mechanisms

The Emerging Role of SGK1 (Serum- and Glucocorticoid-Regulated Kinase 1) in Major Depressive Disorder: Hypothesis and Mechanisms

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