scholarly journals TRIM21 and PHLDA3 Negatively Regulate the Cross-Talk between the PI3K/AKT Pathway and PPP Metabolism

2019 ◽  
Author(s):  
Jie Cheng ◽  
Yan Huang ◽  
Xiaohui Zhang ◽  
Yue Yu ◽  
Wanru Zhang ◽  
...  
Keyword(s):  
Reciprocal Cross ◽  
Cancer Metabolism ◽  
Human Cancer ◽  
Therapeutic Benefit ◽  
Metabolic Reprogramming ◽  
Akt Pathway ◽  
Akt Inhibitor ◽  
Akt Activation ◽  
The Cross

SUMMARYPI3K/AKT signaling is known to regulate cancer metabolism but whether metabolic pathway feedbacks and regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal cross-talks between the PI3K/AKT signal and PPP branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of PPP, by inhibiting a newly identified E3 ligase TIRM21, and promotes PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of an AKT inhibitor PHLDA3. Knockout TRIM21 or PHLDA3 promotes the cross-talks and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of these reciprocal cross-talks may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.

The Mechanisms of Synergistically Cytotoxicity Induced by Homoharringtonine and Aclarubicin in Acute Myeloid Leukemia Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4313-4313
Author(s):  
Lei Wang ◽  
Jie Jin
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Akt Pathway ◽  
Apparent Difference ◽  
Akt Inhibitor ◽  
Simultaneous Exposure ◽  
Acute Myeloid

Abstract Abstract 4313 Previous studies showed HAA regime [HHT (homoharringtonine), cytarabine and ACR (aclarubicin)] resulted in a high complete remission (CR) rate and a better overall survival (OS) rate in patients with primary acute myeloid leukemia. To confirm if a synergistically cytotoxicity was found in AML cells, we investigated the antitumor effect relationship of HHT and ACR against AML cells. Using in vitro system, we demonstrated that simultaneous exposure to HHT and ACR resulted in strong synergistic anti-proliferative effect and apoptosis inducing in AML cells. In vivo, combination of HHT and ACR may be result in a favorable survival in AML xenograft mice. The assay of microarray gene expressing profiling highlighted apparent difference in expression of PI3K gene and WNT3a gene between cells treated by HHT and cells exposure to ACR. Furthermore, decreased expression of PI3K110 and P-AKT protein were observed in AML cells treated with HHT for 3h while no significant change in the expression of two proteins was observed in 90nM of ACR-treated cells. Western Blot analysis also showed ACR could obviously inhibit WNT3a and β-catenin protein levels in AML cells after 3 hours exposure. Although HHT could not inhibit WNT3a protein, it also could apparently down-regulate expression of β-catenin in AML cells. Simultaneous decrease of PI3K signal and WNT3a signal was induced by the combination of HHT and ACR in AML cell lines and primary AML cells. To explore possible targets of synergistically cytotoxity induced by combined HHT/ACR, we silenced wnt3a expression by RNA interference. Then we found suppression of wnt3a expression could enhance the cytotoxity of HHT and AKT inhibitor. Moreover, combining ACR with AKT inhibitor resulted in a synergistically cytotoxic effect too. β-catenin is a shared molecular in both AKT pathway and WNT pathway. Up-regulating of β-catenin expression failed to reduce cell apoptosis induced by HHT plus ACR while partially decrease the growth inhibition rate caused by combining treatment. β-catenin is required for the self-renewal of AML-LSC. Our study also suggests that combining HHT and ACR may synergistically induce apoptosis in LSC-enriched cells. These results indicate that simultaneously inhibiting activity of PI3K/AKT pathway and WNT/β-catenin pathway is a possible mechanism of synergistically cytotoxity induced combinated HHT/ACR in AML cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals p110α Hot Spot Mutations E545K and H1047R Exert Metabolic Reprogramming Independently of p110α Kinase Activity

2015 ◽  
Vol 35 (19) ◽  
pp. 3258-3273 ◽  
Author(s):  
Aditi Chaudhari ◽  
Daniel Krumlinde ◽  
Annika Lundqvist ◽  
Levent M. Akyürek ◽  
Sashidhar Bandaru ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Human Cancer ◽  
Hot Spot ◽  
Metabolic Reprogramming ◽  
Whole Body ◽  
Lipid Kinase ◽  
Glycogen Accumulation ◽  
Adenoviral Gene Transfer ◽  
Hepatic Expression

The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110αin vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.

scholarly journals Sox9-expressing cells promote regeneration after radiation-induced lung injury via PI3K/AKT pathway

2021 ◽  
Author(s):  
Shuang Chen ◽  
Kang Li ◽  
Xinqi Zhong ◽  
Ganping Wang ◽  
Xiaocheng Wang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Background Radiation ◽  
Lineage Tracing ◽  
Akt Pathway ◽  
Therapeutic Effects ◽  
Akt Inhibitor ◽  
Thoracic Radiation ◽  
Radiation Induced ◽  
Epithelium Regeneration

Abstract Background Radiation induced lung injury (RILI) is considered as one of the most common complications of thoracic radiation. Recent studies have focused on stem cells properties to obtain ideal therapeutic effects and Sox9 has been reported to be involved in stem cell induction and differentiation. However, whether Sox9-expressing cells play a role in radiation repair and regeneration remain unknown. Methods We successfully obtain SOX9CreER, RosatdTomato and RosaDTA mice and identify Sox9-expressing cells through lineage tracing assay. Then we evaluated the effects of the ablation of Sox9-expressing cells in vivo. Furthermore, we investigated the underlying mechanism of Sox9 expressing cells during lung regeneration via an online single cell RNA-seq dataset. Results In our study, we demonstrated Sox9-expressing cells promote regenerative of lung tissues and ablation of Sox9-expressing cells leads to severe phenotypes after radiation damage. In addition, analysis of online scRNA-seq dataset revealed an enrichment of PI3K/AKT pathway in Sox9-expressing cells during lung epithelium regeneration. Finally, AKT inhibitor Perifosine could suppress the regenerative effects of Sox9-expressing cells. Conclusions Taken together, our study suggests that Sox9-expressing cells may serve as a therapeutic target in the setting of lung tissue after RILI.

scholarly journals An acetyl-click screening platform identifies a small molecule inhibitor of Histone Acetyltransferase 1 (HAT1) with anti-tumor activity

2021 ◽  
Author(s):  
Joshua J Gruber ◽  
Amith Rangarajan ◽  
Tristan Chou ◽  
Benjamin S. Geller ◽  
Selene Banuelos ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Small Molecule ◽  
Cancer Metabolism ◽  
Human Cancer ◽  
Small Molecule Inhibitor ◽  
Cellular Growth ◽  
Acetyl Coa ◽  
Molecule Inhibitor

HAT1 is a central regulator of chromatin synthesis that acetylates nascent histone H3:H4 tetramers in the cytoplasm. It may have a role in cancer metabolism by linking cytoplasmic production of acetyl-CoA to nuclear acetyl flux. This is because the HAT1 di-acetylation mark is not propagated in chromatin and instead is de-acetylated after nascent histone insertion into chromatin. Thus, HAT1 likely provides a nuclear source of free acetate that may be recycled to acetyl-CoA for nuclear acetylation reactions. Correspondingly, suppression of HAT1 protein expression impairs tumor growth. To ascertain whether targeting HAT1 is a viable anti-cancer treatment strategy we sought to identify small molecule inhibitors of HAT1. We developed a high-throughput HAT1 acetyl-click assay to facilitate drug discovery and enzymology. Screening of small molecules computationally predicted to bind the active site led to the discovery of multiple riboflavin analogs that inhibited HAT1 enzymatic activity by competing with acetyl-CoA binding. These hits were refined by synthesis and testing over 70 analogs, which yielded structure-activity relationships. The isoalloxazine core was required for enzymatic inhibition, whereas modifications of the ribityl sidechain improved enzymatic potency and cellular growth suppression. These efforts resulted in a lead compound (JG-2016) that suppressed growth of human cancer cells lines in vitro and impaired tumor growth in vivo. This is the first report of a small molecule inhibitor of the HAT1 enzyme complex and represents a step towards targeting this pathway for cancer therapy.

scholarly journals Extracellular Vesicles from Adipose-Derived Mesenchymal Stem/Stromal Cells Accelerate Migration and Activate AKT Pathway in Human Keratinocytes and Fibroblasts Independently of miR-205 Activity

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Andrea da Fonseca Ferreira ◽  
Pricila da Silva Cunha ◽  
Virgínia Mendes Carregal ◽  
Priscila de Cássia da Silva ◽  
Marcelo Coutinho de Miranda ◽  
...  
Keyword(s):  
Wound Healing ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Average Diameter ◽  
Skin Wound ◽  
Akt Pathway ◽  
Skin Wound Healing ◽  
Akt Phosphorylation ◽  
Akt Activation

Mesenchymal stem/stromal cells (MSCs) are promising tools in cell therapy. They secrete extracellular vesicles (EVs) that carry different classes of molecules that can promote skin repair, but the mechanisms are poorly understood. Skin wound healing is a complex process that requires the activity of several signaling pathways and cell types, including keratinocytes and fibroblasts. In this study, we explored whether adipose tissue MSC-derived EVs could accelerate migration and proliferation of keratinocytes and fibroblasts, activate the AKT pathway, and promote wound healing in vivo. Furthermore, we evaluated if EV effects are miR-205 dependent. We found that MSC EVs had an average diameter of 135 nm. Keratinocytes and fibroblasts exposed to EVs exhibited higher levels of proliferation, migration, and AKT activation. Topical administration of EVs accelerated skin wound closure. Knockdown of miR-205 decreased AKT phosphorylation in fibroblasts and keratinocytes, whereas migration was decreased only in keratinocytes. Moreover, knockdown of miR-205 failed to inhibit AKT phosphorylation in fibroblasts and keratinocytes exposed to EVs. About the mechanism of EV effects, we found that incubation with EVs prevented inhibition of AKT activation by miR-205 knockdown, suggesting that EVs activate AKT independently of miR-205. In conclusion, we demonstrated that EVs are a promising tool for wound healing.

Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment

2006 ◽  
Vol 24 (11) ◽  
pp. 1770-1783 ◽  
Author(s):  
Geoffrey I. Shapiro
Keyword(s):  
Cell Cycle ◽  
Rna Polymerase Ii ◽  
Cell Cycle Progression ◽  
Tumor Regression ◽  
Human Cancer ◽  
Cell Types ◽  
Therapeutic Benefit ◽  
Cell Cycle Regulators

Cyclin-dependent kinases (cdks) are critical regulators of cell cycle progression and RNA transcription. A variety of genetic and epigenetic events cause universal overactivity of the cell cycle cdks in human cancer, and their inhibition can lead to both cell cycle arrest and apoptosis. However, built-in redundancy may limit the effects of highly selective cdk inhibition. Cdk4/6 inhibition has been shown to induce potent G1 arrest in vitro and tumor regression in vivo; cdk2/1 inhibition has the most potent effects during the S and G2 phases and induces E2F transcription factor–dependent cell death. Modulation of cdk2 and cdk1 activities also affects survival checkpoint responses after exposure to DNA-damaging and microtubule-stabilizing agents. The transcriptional cdks phosphorylate the carboxy-terminal domain of RNA polymerase II, facilitating efficient transcriptional initiation and elongation. Inhibition of these cdks primarily affects the accumulation of transcripts with short half-lives, including those encoding antiapoptosis family members, cell cycle regulators, as well as p53 and nuclear factor-kappa B–responsive gene targets. These effects may account for apoptosis induced by cdk9 inhibitors, especially in malignant hematopoietic cells, and may also potentiate cytotoxicity mediated by disruption of a variety of pathways in many transformed cell types. Current work is focusing on overcoming pharmacokinetic barriers that hindered development of flavopiridol, a pan-cdk inhibitor, as well as assessing novel classes of compounds potently targeting groups of cell cycle cdks (cdk4/6 or cdk2/1) with variable effects on the transcriptional cdks 7 and 9. These efforts will establish whether the strategy of cdk inhibition is able to produce therapeutic benefit in the majority of human tumors.

scholarly journals Pseudomonas aeruginosaflagellar motility activates the phagocyte PI3K/Akt pathway to induce phagocytic engulfment

2014 ◽  
Vol 306 (7) ◽  
pp. L698-L707 ◽  
Author(s):  
Rustin R. Lovewell ◽  
Sandra M. Hayes ◽  
George A. O'Toole ◽  
Brent Berwin
Keyword(s):  
Actin Polymerization ◽  
Bacterial Pathogen ◽  
Akt Pathway ◽  
Flagellar Motility ◽  
Akt Activation ◽  
Molecular Pattern ◽  
Primary Means ◽  
Bacterial Uptake ◽  
Cellular Signaling Pathway

Phagocytosis of the bacterial pathogen Pseudomonas aeruginosa is the primary means by which the host controls bacterially induced pneumonia during lung infection. Previous studies have identified flagellar swimming motility as a key pathogen-associated molecular pattern (PAMP) recognized by phagocytes to initiate engulfment. Correspondingly, loss of flagellar motility is observed during chronic pulmonary infection with P. aeruginosa, and this likely reflects a selection for bacteria resistant to phagocytic clearance. However, the mechanism underlying the preferential phagocytic response to motile bacteria is unknown. Here we have identified a cellular signaling pathway in alveolar macrophages and other phagocytes that is specifically activated by flagellar motility. Genetic and biochemical methods were employed to identify that phagocyte PI3K/Akt activation is required for bacterial uptake and, importantly, it is specifically activated in response to P. aeruginosa flagellar motility. Based on these observations, the second important finding that emerged from these studies is that titration of the bacterial flagellar motility results in a proportional activation state of Akt. Therefore, the Akt pathway is responsive to, and corresponds with, the degree of bacterial flagellar motility, is independent of the actin polymerization that facilitates phagocytosis, and determines the phagocytic fate of P. aeruginosa. These findings elucidate the mechanism behind motility-dependent phagocytosis of extracellular bacteria and support a model whereby phagocytic clearance exerts a selective pressure on P. aeruginosa populations in vivo, which contributes to changes in pathogenesis during infections.

scholarly journals Fundamentals of cancer metabolism

2016 ◽  
Vol 2 (5) ◽  
pp. e1600200 ◽  
Author(s):  
Ralph J. DeBerardinis ◽  
Navdeep S. Chandel
Keyword(s):  
Conceptual Framework ◽  
Tumor Cells ◽  
Recent Work ◽  
Cancer Metabolism ◽  
Human Cancer ◽  
Metabolic Reprogramming ◽  
Malignant Cells ◽  
Hallmarks Of Cancer ◽  
Altered Metabolism ◽  
New Strategies

Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.

scholarly journals SARS-CoV-2 and Glutamine: SARS-CoV-2 Triggered Pathogenesis via Metabolic Reprograming of Glutamine in Host Cells

2021 ◽  
Vol 7 ◽  
Author(s):  
Shiv Bharadwaj ◽  
Mahendra Singh ◽  
Nikhil Kirtipal ◽  
Sang Gu Kang
Keyword(s):  
Cancer Metabolism ◽  
Viral Infections ◽  
Mammalian Target Of Rapamycin ◽  
Metabolic Reprogramming ◽  
Host Cells ◽  
Glutamine Metabolism ◽  
Altered Glucose

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as coronavirus disease 2019 (COVID-19) pandemic, has killed more than a million people worldwide, and researchers are constantly working to develop therapeutics in the treatment and prevention of this new viral infection. To infect and induced pathogenesis as observed in other viral infections, we postulated that SARS-CoV-2 may also require an escalation in the anabolic metabolism, such as glucose and glutamine, to support its energy and biosynthetic requirements during the infection cycle. Recently, the requirement of altered glucose metabolism in SARS-CoV-2 pathogenesis was demonstrated, but the role of dysregulated glutamine metabolism is not yet mentioned for its infection. In this perspective, we have attempted to provide a summary of possible biochemical events on putative metabolic reprograming of glutamine in host cells upon SARS-CoV-2 infection by comparison to other viral infections/cancer metabolism and available clinical data or research on SARS-CoV-2 pathogenesis. This systematic hypothesis concluded the vital role of glutaminase-1 (GLS1), phosphoserine aminotransferase (PSAT1), hypoxia-inducible factor-1 alpha (HIF-1α), mammalian target of rapamycin complex 1 (mTORC1), glutamine-fructose amidotransferase 1/2 (GFAT1/2), and transcription factor Myc as key cellular factors to mediate and promote the glutamine metabolic reprogramming in SARS-CoV-2 infected cells. In absence of concrete data available for SARS-CoV-2 induced metabolic reprogramming of glutamine, this study efforts to connect the gaps with available clinical shreds of evidence in SARS-CoV-2 infection with altered glutamine metabolism and hopefully could be beneficial in the designing of strategic methods for therapeutic development with elucidation using in vitro or in vivo approaches.

Constitutive Activation of AKT Contributes to the Pathogenesis and Survival of Blastoid Variants of Mantle Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1908-1908
Author(s):  
Martina Rudelius ◽  
Stefania Pittaluga ◽  
Trinh H.-T. Pham ◽  
Thomas Fountaine ◽  
Leticia Quintanilla-Martinez ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Regulatory Proteins ◽  
Akt Pathway ◽  
Akt Inhibitor ◽  
Akt Activation ◽  
Constitutive Activation ◽  
Mantle Cell

Abstract The serine/threonine protein kinase AKT [protein kinase B (PKB)] plays a pivotal role in the tumorigenesis of many human malignancies, including hematopoietic neoplasms. AKT mediates cancer cell survival and cell growth through the phosphorylation of key regulatory proteins such as FRKHL-1, MDM2 and p27. We wished to determine whether the AKT signaling pathway might be involved in the pathogenesis of mantle cell lymphoma (MCL).The activated form of AKT (pAKT) and phosphorylation of several AKT targets, including FRKHL-1, MDM2 and p27 as well as the upstream modulators PTEN and TCL-1 were analyzed by immunoblotting in 31 MCL cases (16 classic MCL and 15 MCL of the blastoid variant) and in four MCL cell lines (Granta 519, NCEB, REC-1 and Z138). PI3KCA mutation analysis at two hotspot regions (Exons 9 and 20) were completed for all cases and cell lines. Subsequently, inhibition of the PIK3/AKT-pathway with LY294002, Wortmannin and AKT-inhibitor was performed in the four cell lines. pAKT was expressed in all 15 blastoid variants of MCL and in the 4 cell lines, with high expression in 13/15 cases and low expression in 2/15 cases. In contrast, only 2/16 typical MCL expressed pAKT, at low levels. Furthermore, pAKT expression in the blastoid variants and cell lines was accompanied by the phosphorylation of multiple downstream targets of activated AKT, including the cell cycle regulatory proteins p27, FRKHL-1, MDM-2 and the apoptosis associated protein bad. 42% of the blastoid MCL cases showed loss of PTEN, while only 2 (12%) of the typical cases showed diminished PTEN expression.TCL-1 expression levels were not correlated with AKT activation and no mutations of PI3KCA were detected. Functional studies of all four MCL lines demonstrated that the phosphorylation of the downstream effectors were regulated by activated AKT:Inhibition of the PI3K/AKT pathway by both 20 μM LY294002 and 8 μM Wortmannin or 40 μM AKT-inhibitor abrogated the phosphorylation of AKT, p27, FRKHL-1, bad and MDM2 after 24 to 48 hours of treatment, and resulted in G1 arrest after 24 hours of treatment and measurable apoptosis by 48 hours. We conclude that constitutive activation of AKT contributes to the pathogenesis of the blastoid variants of MCL. One possible mechanism of AKT activation is the loss of PTEN expression. The inhibition of the PIK3/AKT pathway in MCL cell lines leads to induction of cell cycle arrest and apoptosis, raising the possibility that PI3K/AKT inhibitors may be effective in the treatment of aggressive (blastoid) variants of MCLs.

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