The unique Akt inhibitor SC66 suppressed AMPK activity and abolished autophagy through the EGFR‐p62 pathway

2021 ◽  
Author(s):  
Bolin Hou ◽  
Erwei Li ◽  
Jingnan Liang ◽  
Shuchun Liu ◽  
Huaiyi Yang ◽  
...  
Keyword(s):  
Akt Inhibitor ◽  
Ampk Activity

scholarly journals GSK3β-dependent inhibition of AMPK potentiates activation of neutrophils and macrophages and enhances severity of acute lung injury

2014 ◽  
Vol 307 (10) ◽  
pp. L735-L745 ◽  
Author(s):  
Dae Won Park ◽  
Shaoning Jiang ◽  
Yanping Liu ◽  
Gene P. Siegal ◽  
Ken Inoki ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Responses ◽  
Akt Inhibitor ◽  
Tnf Α ◽  
Dependent Inhibition ◽  
Ampk Activity ◽  
Sirna Knockdown ◽  
Amp Activated Protein Kinase

Although AMP-activated protein kinase (AMPK) is involved in regulating carbohydrate and lipid metabolism, activated AMPK also plays an anti-inflammatory role in many cell populations. However, despite the ability of AMPK activation to diminish the severity of inflammatory responses, previous studies have found that AMPK activity is diminished in LPS-treated neutrophils and also in lungs of mice with LPS-induced acute lung injury (ALI). Since GSK3β participates in regulating AMPK activity, we examined potential roles for GSK3β in modulating LPS-induced activation of neutrophils and macrophages and in influencing severity of ALI. We found that GSK3β-dependent phosphorylation of T479-AMPK was associated with pT172 dephosphorylation and inactivation of AMPK following TLR4 engagement. GSK3β inhibitors BIO (6-bromoindirubin-3′-oxime), SB216763 , or siRNA knockdown of GSK3β, but not the PI3K/AKT inhibitor LY294002, prevented Thr172-AMPK dephosphorylation. Exposure to LPS resulted in rapid binding between IKKβ and AMPKα, and phosphorylation of S485-AMPK by IKKβ. These results suggest that IKKβ-dependent phosphorylation of S485-AMPK was an essential step in subsequent phosphorylation and inactivation AMPK by GSK3β. Inhibition of GSK3β activity delayed IκBα degradation and diminished expression of the proinflammatory TNF-α in LPS-stimulated neutrophils and macrophages. In vivo, inhibition of GSK3β decreased the severity of LPS-induced lung injury as assessed by development of pulmonary edema, production of TNF-α and MIP-2, and release of the alarmins HMGB1 and histone 3 in the lungs. These results show that inhibition of AMPK by GSK3β plays an important contributory role in enhancing LPS-induced inflammatory responses, including worsening the severity of ALI.

scholarly journals Reducing NADPH Synthesis Counteracts Diabetic Nephropathy through Restoration of AMPK Activity in Type 1 Diabetic Rats

Cell Reports ◽  
2020 ◽  
Vol 32 (13) ◽  
pp. 108207
Author(s):  
Xiao Wei ◽  
Zongshi Lu ◽  
Li Li ◽  
Hexuan Zhang ◽  
Fang Sun ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Diabetic Rats ◽  
Ampk Activity

scholarly journals Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non–BRCA1/2-Mutant Cancers

2020 ◽  
Vol 10 (10) ◽  
pp. 1528-1543 ◽  
Author(s):  
Timothy A. Yap ◽  
Rebecca Kristeleit ◽  
Vasiliki Michalarea ◽  
Stephen J. Pettitt ◽  
Joline S.J. Lim ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Parp Inhibitor ◽  
Akt Inhibitor

scholarly journals Retraction Note to: The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells

2021 ◽  
Author(s):  
M. Mandal ◽  
S. Kim ◽  
M. N. Younes ◽  
S. A. Jasser ◽  
A. K. El-Naggar ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Cancer Cells ◽  
Akt Inhibitor ◽  
Thyroid Cancer Cells

scholarly journals Kog1/Raptor mediates metabolic rewiring during nutrient limitation by controlling SNF1/AMPK activity

2021 ◽  
Vol 7 (16) ◽  
pp. eabe5544
Author(s):  
Zeenat Rashida ◽  
Rajalakshmi Srinivasan ◽  
Meghana Cyanam ◽  
Sunil Laxman
Keyword(s):  
Amino Acid ◽  
Nutrient Limitation ◽  
Carbon Flux ◽  
Metabolic Flux ◽  
Carbon Allocation ◽  
Carbon Utilization ◽  
Acid Biosynthesis ◽  
Control Growth ◽  
Ampk Activity ◽  
Delayed Growth

In changing environments, cells modulate resource budgeting through distinct metabolic routes to control growth. Accordingly, the TORC1 and SNF1/AMPK pathways operate contrastingly in nutrient replete or limited environments to maintain homeostasis. The functions of TORC1 under glucose and amino acid limitation are relatively unknown. We identified a modified form of the yeast TORC1 component Kog1/Raptor, which exhibits delayed growth exclusively during glucose and amino acid limitations. Using this, we found a necessary function for Kog1 in these conditions where TORC1 kinase activity is undetectable. Metabolic flux and transcriptome analysis revealed that Kog1 controls SNF1-dependent carbon flux apportioning between glutamate/amino acid biosynthesis and gluconeogenesis. Kog1 regulates SNF1/AMPK activity and outputs and mediates a rapamycin-independent activation of the SNF1 targets Mig1 and Cat8. This enables effective glucose derepression, gluconeogenesis activation, and carbon allocation through different pathways. Therefore, Kog1 centrally regulates metabolic homeostasis and carbon utilization during nutrient limitation by managing SNF1 activity.

scholarly journals Overexpression of Activated AMPK in the Anopheles stephensi Midgut Impacts Mosquito Metabolism, Reproduction and Plasmodium Resistance

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 119
Author(s):  
Chioma Oringanje ◽  
Lillian R. Delacruz ◽  
Yunan Han ◽  
Shirley Luckhart ◽  
Michael A. Riehle
Keyword(s):  
Egg Production ◽  
Anopheles Stephensi ◽  
Mitochondrial Dynamics ◽  
Adult Life ◽  
Blood Feeding ◽  
Pathogen Resistance ◽  
Α Subunit ◽  
Significant Difference ◽  
Transgenic Lines ◽  
Ampk Activity

Mitochondrial integrity and homeostasis in the midgut are key factors controlling mosquito fitness and anti-pathogen resistance. Targeting genes that regulate mitochondrial dynamics represents a potential strategy for limiting mosquito-borne diseases. AMP-activated protein kinase (AMPK) is a key cellular energy sensor found in nearly all eukaryotic cells. When activated, AMPK inhibits anabolic pathways that consume ATP and activates catabolic processes that synthesize ATP. In this study, we overexpressed a truncated and constitutively active α-subunit of AMPK under the control of the midgut-specific carboxypeptidase promotor in the midgut of female Anopheles stephensi. As expected, AMPK overexpression in homozygous transgenic mosquitoes was associated with changes in nutrient storage and metabolism, decreasing glycogen levels at 24 h post-blood feeding when transgene expression was maximal, and concurrently increasing circulating trehalose at the same time point. When transgenic lines were challenged with Plasmodium falciparum, we observed a significant decrease in the prevalence and intensity of infection relative to wild type controls. Surprisingly, we did not observe a significant difference in the survival of adult mosquitoes fed either sugar only or both sugar and bloodmeals throughout adult life. This may be due to the limited period that the transgene was activated before homeostasis was restored. However, we did observe a significant decrease in egg production, suggesting that manipulation of AMPK activity in the mosquito midgut resulted in the re-allocation of resources away from egg production. In summary, this work identifies midgut AMPK activity as an important regulator of metabolism, reproduction, and innate immunity in An. stephensi, a highly invasive and important malaria vector species.

scholarly journals Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 480
Author(s):  
Rakshitha Pandulal Miskin ◽  
Janine S. A. Warren ◽  
Abibatou Ndoye ◽  
Lei Wu ◽  
John M. Lamar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Cell Invasion ◽  
Breast Cancer Cells ◽  
Gene Promoter ◽  
Akt Inhibitor ◽  
Integrin Α3β1

In the current study, we demonstrate that integrin α3β1 promotes invasive and metastatic traits of triple-negative breast cancer (TNBC) cells through induction of the transcription factor, Brain-2 (Brn-2). We show that RNAi-mediated suppression of α3β1 in MDA-MB-231 cells caused reduced expression of Brn-2 mRNA and protein and reduced activity of the BRN2 gene promoter. In addition, RNAi-targeting of Brn-2 in MDA-MB-231 cells decreased invasion in vitro and lung colonization in vivo, and exogenous Brn-2 expression partially restored invasion to cells in which α3β1 was suppressed. α3β1 promoted phosphorylation of Akt in MDA-MB-231 cells, and treatment of these cells with a pharmacological Akt inhibitor (MK-2206) reduced both Brn-2 expression and cell invasion, indicating that α3β1-Akt signaling contributes to Brn-2 induction. Analysis of RNAseq data from patients with invasive breast carcinoma revealed that high BRN2 expression correlates with poor survival. Moreover, high BRN2 expression positively correlates with high ITGA3 expression in basal-like breast cancer, which is consistent with our experimental findings that α3β1 induces Brn-2 in TNBC cells. Together, our study demonstrates a pro-invasive/pro-metastatic role for Brn-2 in breast cancer cells and identifies a role for integrin α3β1 in regulating Brn-2 expression, thereby revealing a novel mechanism of integrin-dependent breast cancer cell invasion.

scholarly journals Impact of calcitriol and an AKT inhibitor, AT7867, on survival of rat C6 glioma cells

2021 ◽  
Vol 35 (1) ◽  
pp. 730-738
Author(s):  
Ozlem Kucukhuseyin ◽  
Aris Cakiris ◽  
Mehmet Tolgahan Hakan ◽  
Cem Horozoglu ◽  
Erdem Tuzun ◽  
...  
Keyword(s):  
Glioma Cells ◽  
C6 Glioma ◽  
C6 Glioma Cells ◽  
Akt Inhibitor ◽  
Rat C6 Glioma
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