Inhibition of serum and glucocorticoid regulated kinases by GSK650394 reduced infarct size in early cerebral ischemia-reperfusion with decreased BBB disruption

Z., Oak; Chiricolo, Antonio; Liu, Xia; Patel, Nikhil; Jacinto, Estela; Weiss, Harvey R.

doi:10.1016/j.neulet.2021.136143

“…GSK-650394 has been validated in in vitro models to attenuate cerebral ischemia-reperfusion injury. [ 31 – 33 ] Related studies have shown that GSK-650394 exhibits antitumor activity in established breast cancer cell lines in vitro and in vivo [ 56 ]. Application of GSK-650394 to attenuates breast cancer lung metastasis in mice [ 57 ], and we wondered whether GSK-650394 had similar efficacy in CRLM.…”

Section: Resultsmentioning

confidence: 99%

“…SGK1 activation is involved in pathophysiological processes including inflammation and tumorigenesis [ 29 , 30 ]. In a mouse model, administration of an SGK1 inhibitor (GSK-650394) reduced cerebral ischemia–reperfusion injury [ 31 , 32 ]. In a rat model of global cerebral ischemia, administration of GSK-650394 was noted to improve the learning and memory deficits caused by cerebral ischemia in rats [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3

Li

¹

,

Wang

²

,

Jiao

³

et al. 2023

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Background Liver metastasis is the leading cause of death in patients with colorectal cancer (CRC). Surgical resection of the liver metastases increases the incidence of long-term survival in patients with colorectal liver metastasis (CRLM). However, many patients experience CRLM recurrence after the initial liver resection. As an unavoidable pathophysiological process in liver surgery, liver ischemia-reperfusion (IR) injury increases the risk of tumor recurrence and metastasis. Methods Colorectal liver metastasis (CRLM) mouse models and mouse liver partial warm ischemia models were constructed. The levels of lipid peroxidation were detected in cells or tissues. Western Blot, qPCR, elisa, immunofluorescence, immunohistochemistry, scanning electron microscope, flow cytometry analysis were conducted to evaluate the changes of multiple signaling pathways during CRLM recurrence under liver ischemia-reperfusion (IR) background, including SGK1/IL-6/STAT3, neutrophil extracellular traps (NETs) formation, polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) infiltration. Results Hepatocyte serum/glucocorticoid regulated kinase 1 (SGK1) was activated in response to hepatic ischemia-reperfusion injury to pass hepatocyte STAT3 phosphorylation and serum amyloid A (SAA) hyperactivation signals in CRLM-IR mice, such regulation is dependent on SGK-activated IL-6 autocrine. Administration of the SGK1 inhibitor GSK-650394 further reduced ERK-related neutrophil extracellular traps (NETs) formation and polymorphonucler myeloid-derived suppressor cells (PMN-MDSC) infiltration compared with targeting hepatocyte SGK1 alone, thereby alleviating CRLM in the context of IR. Conclusions Our study demonstrates that hepatocyte and immune cell SGK1 synergistically promote postoperative CRLM recurrence in response to hepatic IR stress, and identifies SGK1 as a translational target that may improve postoperative CRLM recurrence.

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“…52 GSK-650394 has been validated in in vitro models to attenuate cerebral ischemia-reperfusion injury. [31][32][33] Related studies have shown that GSK-650394 exhibits antitumor activity in established breast cancer cell lines in vitro and in vivo. 53 Application of GSK-650394 to attenuates breast cancer lung metastasis in mice, 54 and we wondered whether GSK-650394 had similar e cacy in CRLM.…”

Section: Gsk-650394 Regulates Nets Formation In Crlm Mice With Ir Bac...mentioning

confidence: 99%

“…29,30 In a mouse model, administration of an SGK1 inhibitor (GSK-650394) reduced cerebral ischemia-reperfusion injury. 31,32 In a rat model of global cerebral ischemia, administration of GSK-650394 was noted to improve the learning and memory de cits caused by cerebral ischemia in rats. 33 SGK1 plays an important role in tumorigenesis, proliferation, apoptosis, invasion, metastasis and autophagy processes.…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3

Li

¹

,

Wang

²

,

Jiao

³

et al. 2022

Preprint

1

0

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Background Liver metastasis is the leading cause of death in patients with colorectal cancer (CRC). Surgical resection of the liver metastases increases the incidence of long-term survival in patients with colorectal liver metastasis (CRLM). However, many patients experience CRLM recurrence after the initial liver resection. As an unavoidable pathophysiological process in liver surgery, liver ischemia-reperfusion (IR) injury increases the risk of tumor recurrence and metastasis. Methods Colorectal liver metastasis (CRLM) mouse models and mouse liver partial warm ischemia models were constructed. The levels of lipid peroxidation were detected in cells or tissues. Western Blot, qPCR, elisa, immunofluorescence, immunohistochemistry, scanning electron microscope, flow cytometry analysis were conducted to evaluate the changes of multiple signaling pathways during CRLM recurrence under liver ischemia-reperfusion (IR) background, including SGK1/IL-6/STAT3, neutrophil extracellular traps (NETs) formation, polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) infiltration. Results Hepatocyte serum/glucocorticoid regulated kinase 1 (SGK1) was activated in response to hepatic ischemia-reperfusion injury to pass hepatocyte STAT3 phosphorylation and serum amyloid A (SAA) hyperactivation signals in CRLM-IR mice, such regulation is dependent on SGK-activated IL-6 autocrine. Administration of the SGK1 inhibitor GSK-650394 further reduced ERK-related neutrophil extracellular traps (NETs) formation and polymorphonucler myeloid-derived suppressor cells (PMN-MDSC) infiltration compared with targeting hepatocyte SGK1 alone, thereby alleviating CRLM in the context of IR. Conclusions Our study demonstrates that hepatocyte and immune cell SGK1 synergistically promote postoperative CRLM recurrence in response to hepatic IR stress, and identifies SGK1 as a translational target that may improve postoperative CRLM recurrence.

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“…Until recently, very few CaMKK2 inhibitors had been reported; the most notable are STO-609 and GSK650394 , (Figure ), which have enabled seminal publications. − Still, challenges are associated with these molecules’ physiochemical properties and kinase selectivity, which diminish their utility as tools. In 2021, Eduful et al reported a comprehensive scaffold hopping exercise to identify selective CaMKK2 binders .…”

Section: Introductionmentioning

confidence: 99%

Identification of Small Molecule Inhibitors and Ligand Directed Degraders of Calcium/Calmodulin Dependent Protein Kinase Kinase 1 and 2 (CaMKK1/2)

Chen,

Whitefield,

Nevius

et al. 2023

J. Med. Chem.

0

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Inhibition of serum and glucocorticoid regulated kinases by GSK650394 reduced infarct size in early cerebral ischemia-reperfusion with decreased BBB disruption

Cited by 8 publications

References 39 publications

Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3

Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3

Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3

Identification of Small Molecule Inhibitors and Ligand Directed Degraders of Calcium/Calmodulin Dependent Protein Kinase Kinase 1 and 2 (CaMKK1/2)

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