Polyamine production is downstream and upstream of oncogenic PI3K signalling and contributes to tumour cell growth

2013 ◽  
Vol 450 (3) ◽  
pp. 619-628 ◽  
Author(s):  
Vinothini Rajeeve ◽  
Wayne Pearce ◽  
Marta Cascante ◽  
Bart Vanhaesebroeck ◽  
Pedro R. Cutillas
Keyword(s):  
Cell Survival ◽  
Cancer Cells ◽  
Ornithine Decarboxylase ◽  
Small Molecule ◽  
Xenograft Model ◽  
Pi3k Pathway ◽  
Pik3ca Mutations ◽  
Akt Phosphorylation ◽  
Pi3k Signalling ◽  
Phosphoinositide 3 Kinase

PI3K (phosphoinositide 3-kinase) signalling pathways regulate a large array of cell biological functions in normal and cancer cells. In the present study we investigated the involvement of PI3K in modulating small molecule metabolism. A LC (liquid chromatography)-MS screen in colorectal cancer cell lines isogenic for oncogenic PIK3CA mutations revealed an association between PI3K activation and the levels of polyamine pathway metabolites, including 5-methylthioadenosine, putrescine and spermidine. Pharmacological inhibition confirmed that the PI3K pathway controls polyamine production. Despite inducing a decrease in PKB (protein kinase B)/Akt phosphorylation, spermidine promoted cell survival and opposed the anti-proliferative effects of PI3K inhibitors. Conversely, polyamine depletion by an ornithine decarboxylase inhibitor enhanced PKB/Akt phosphorylation, but suppressed cell survival. These results suggest that spermidine mediates cell proliferation and survival downstream of PI3K/Akt and indicate that these two biochemical pathways control each other's activities, highlighting a mechanism by which small molecule metabolism feeds back to regulate kinase signalling. Consistent with this feedback loop having a functional role in these cell models, pharmacological inhibitors of PI3K and ornithine decarboxylase potentiated each other in inhibiting tumour growth in a xenograft model. The results of the present study support the notion that the modulation of spermidine concentrations may be a previously unrecognized mechanism by which PI3K sustains chronic proliferation of cancer cells.

Phosphoinositide-3-Kinase Inhibition Enhances Radiosensitization of Cervical Cancer In Vivo

2011 ◽  
Vol 21 (1) ◽  
pp. 100-105 ◽  
Author(s):  
Yi Liu ◽  
Baoxia Cui ◽  
Yunbo Qiao ◽  
Yan Zhang ◽  
Yongju Tian ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Kinase Inhibition ◽  
Clonogenic Assays ◽  
Akt Phosphorylation ◽  
Pi3k Activity ◽  
Pi3k Inhibition ◽  
Tumor Regrowth ◽  
Phosphoinositide 3 Kinase

Background:Phosphoinositide-3-kinase (PI3K)/Akt pathway is downregulated in several human cancers, and PI3K inhibition can sensitize these cancer cells to radiation. However, no research on cervical cancer in vivo has been reported. The present study further investigated whether PI3K inhibition could sensitize cervical cancer to radiation in vivo.Methods:HeLa cells with sustained PI3K activity and Akt phosphorylation were injected subcutaneously into BALB/C nude mice to establish tumor cell xenograft, which were randomly assigned to control, PI3K inhibitor LY294002 alone, radiation alone, or combined LY294002 and radiation group. Akt phosphorylation was detected by Western blotting to evaluate the blocking efficiency on PI3K activity. The radiosensitization of PI3K inhibition was measured by clonogenic assays, apoptosis analysis, and tumor regrowth assays.Results:The combination of LY294002 and radiation resulted in significant and synergistic suppression of cervical cancer cells in a dose-dependent manner in clonogenic assays (P< 0.05), higher ratio of apoptosis cells, and more remarkable reduction of Akt phosphorylation. Tumor regrowth delay curve showed the lowest increase of tumor volume in the combined group (37 days in average) (P= 0.003). Besides, LY294002 (100 mg/kg) alone decreased cell survival and produced xenograft regrowth delay.Conclusions:Phosphoinositide-3-kinase inhibition by LY294002 can synergistically enhance radiation efficacy via dephosphorylation of Akt in cervical cancer, and PI3K inhibition alone can also suppress tumor regrowth. This may provide novel therapeutic opportunities to enhance the effect of radiotherapy against cervical cancer.

scholarly journals Anticancer activity of pyrithione zinc in oral cancer cells identified in small molecule screens and xenograft model: Implications for oral cancer therapy

2015 ◽  
Vol 9 (8) ◽  
pp. 1720-1735 ◽  
Author(s):  
Gunjan Srivastava ◽  
Ajay Matta ◽  
Guodong Fu ◽  
Raj Thani Somasundaram ◽  
Alessandro Datti ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Oral Cancer ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Small Molecule ◽  
Xenograft Model ◽  
Oral Cancer Cells

PI3K signalling during influenza A virus infections

2007 ◽  
Vol 35 (2) ◽  
pp. 186-187 ◽  
Author(s):  
B.G. Hale ◽  
R.E. Randall
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Pi3k Pathway ◽  
Regulatory Subunit ◽  
Ns1 Protein ◽  
Virus Infections ◽  
Influenza A Viruses ◽  
Pi3k Signalling ◽  
Novel Target ◽  
Phosphoinositide 3 Kinase

Recent work has demonstrated that the PI3K (phosphoinositide 3-kinase) signalling pathway is important for efficient influenza A virus replication. Activation of PI3K in virus-infected cells is mediated by the viral NS1 protein, which binds directly to the p85β regulatory subunit of PI3K and causes the PI3K-dependent phosphorylation of Akt (protein kinase B). Given that recombinant influenza A viruses unable to activate PI3K signalling are attenuated in tissue culture, the PI3K pathway could be a novel target for the development of future anti-influenza drugs.

scholarly journals The biomechanical context influences the output signaling, independently of PIK3CA mutations in breast cancer cells.

2021 ◽  
Author(s):  
Mickael Di-Luoffo ◽  
Morgan Delarue ◽  
Julie Guillermet-Guibert
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Compressive Stress ◽  
Breast Cancer Cells ◽  
Pi3k Pathway ◽  
Matrix Remodeling ◽  
Specific Class ◽  
Pik3ca Mutations ◽  
Pi3k Activation ◽  
Signaling Activation

Mechanical stresses including tensile and compressive stresses are ubiquitous in na-ture, and are now well-recognized as being inherent to the development of most cancers. They are integrated by mechanotransduction in cells. Tensile stress is largely associated with YAP/TAZ pathway activation. However, less is known about signaling induced by compressive stress, the latter arising from extracellular matrix remodeling and local tumor growth. In the present study, we used transcriptomic data obtained after unidirectional compression of wild-type and mutant PIK3CA breast cancer cells from Kim et al., 2019. We analyzed in an unbiased manner signatures of cell signaling activation including phosphoinositide 3-kinases (PI3Ks) activity pathway in response to compressive stress. Because we found that PI3K activation occurred upon compression, we studied PI3K isoform-specific pathways using known transcriptional targets of PI3Kα inhibitor (BYL719) or of PI3Kβ inhibitor (AZD8186). Our study provides transcriptomic evidences for the role of PI3K pathway in compression-induced mechanotransduction, through the roles of isoform-specific class I PI3Ks and independently of PIK3CA alterations. In a compressive environment, the canonical pathways (YAP/TAZ and Piezo) was not increased, while other targetable mechanisms, such as PI3K signal or autophagy, may provide a proliferative advantage and increased cell resistance to chemotherapies.

scholarly journals MicroRNAs’ control of cancer cell dormancy

Cell Division ◽  
2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Tatiana G. Ruksha
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Pi3k Pathway ◽  
Chemotherapeutic Agents ◽  
Quiescent State ◽  
Cell Cycle Regulators ◽  
Phosphoinositide 3 Kinase ◽  
Cells Of The Microenvironment ◽  
Tumor Types ◽  
Cell Dormancy

Abstract ‘Dormancy’, in the context of carcinogenesis, is a biological phenomenon of decreased cancer cell proliferation and metabolism. In view of their ability to remain quiescent, cancer cells are able to avoid cell death induced by chemotherapeutic agents, and thereby give rise to tumor relapse at a later stage. Being a dynamic event, the dormant state is controlled by several epigenetic mechanisms, including the action of microRNAs. The present review highlights microRNAs that have been shown to be dysregulated in dormant cancer cells among different tumor types. MicroRNAs accomplish their control of cancer cell quiescence by targeting cell cycle regulators and signaling pathways involved in cell growth maintenance, including the AKT/phosphoinositide 3-kinase (PI3K) pathway. MicroRNAs, as components of intercellular vesicles, enable interactions to occur between cancer cells and cells of the microenvironment, resulting in the cancer cells either acquiring the quiescent state or, oppositely, stimulating them to proliferate. Taken together, the evidence obtained to date has collectively confirmed the involvement of microRNAsin cancer cell dormancy. Modulation of the various processes may enable optimization of the treatment of metastatic tumors.

scholarly journals Environmental and sex-specific molecular signatures of glioma causation

2021 ◽  
Author(s):  
Elizabeth B Claus ◽  
Vincent L Cannataro ◽  
Stephen G Gaffney ◽  
Jeffrey P Townsend
Keyword(s):  
Environmental Risk ◽  
Pi3k Pathway ◽  
Braf V600e ◽  
Molecular Signature ◽  
Sequencing Data ◽  
Pik3ca Mutations ◽  
Coding Regions ◽  
Age Related ◽  
Males And Females ◽  
Phosphoinositide 3 Kinase

Abstract Background The relative importance of genetic and environmental risk factors in gliomagenesis remains uncertain. Methods Using whole-exome sequencing data from 1105 adult gliomas, we evaluate the relative contribution to cancer cell lineage proliferation and survival of single-nucleotide mutations in tumors by IDH mutation subtype and sex. We also quantify the contributions of COSMIC cancer mutational signatures to these tumors, identifying possible risk exposures. Results IDH-mutant tumors exhibited few unique recurrent substitutions—all in coding regions, while IDH-wildtype tumors exhibited many substitutions in non-coding regions. The importance of previously reported mutations in IDH1/2, TP53, EGFR, PTEN, PIK3CA and PIK3R1 was confirmed; however, the largest cancer effect in IDH wildtype tumors was associated with mutations in the low-prevalence BRAF V600E. Males and females exhibited mutations in a similar set of significantly overburdened genes, with some differences in variant sites—notably in the phosphoinositide 3-kinase (PI3K) pathway. In IDH-mutant tumors, PIK3CA mutations were located in the helical domain for females and the kinase domain for males; variants of import also differed by sex for PIK3R1. Endogenous age-related mutagenesis was the primary molecular signature identified; a signature associated with exogenous exposure to haloalkanes was identified and noted more frequently in males. Conclusions Cancer-causing mutations in glioma primarily originated as a consequence of endogenous rather than exogenous factors. Mutations in helical versus kinase domains of genes in the phosphoinositide 3-kinase (PI3K) pathway are differentially selected in males and females. Additionally, a rare environmental risk factor is suggested for some cases of glioma— particularly in males.

Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 1942-1949 ◽  
Author(s):  
Christopher J. Ong ◽  
Andrew Ming-Lum ◽  
Matt Nodwell ◽  
Ali Ghanipour ◽  
Lu Yang ◽  
...  
Keyword(s):  
Small Molecule ◽  
Hematopoietic Cells ◽  
Pi3k Pathway ◽  
Cellular Activation ◽  
Phosphoinositide 3 Kinase ◽  
Identification And Characterization ◽  
Kinase Pathway

Abstract Because phosphoinositide 3-kinase (PI3K) plays a central role in cellular activation, proliferation, and survival, pharmacologic inhibitors targeting components of the PI3K pathway are actively being developed as therapeutics for the treatment of inflammatory disorders and cancer. These targeted drugs inhibit the activity of either PI3K itself or downstream protein kinases. However, a previously unexplored, alternate strategy is to activate the negative regulatory phosphatases in this pathway. The SH2-containing inositol-5′-phosphatase SHIP1 is a normal physiologic counter-regulator of PI3K in immune/hematopoietic cells that hydrolyzes the PI3K product phosphatidylinositiol-3,4,5-trisphosphate (PIP3). We now describe the identification and characterization of potent and specific small-molecule activators of SHIP1. These compounds represent the first small-molecule activators of a phosphatase, and are able to activate recombinant SHIP1 enzyme in vitro and stimulate SHIP1 activity in intact macrophage and mast cells. Mechanism of activation studies with these compounds suggest that they bind a previously undescribed, allosteric activation domain within SHIP1. Furthermore, in vivo administration of these compounds was protective in mouse models of endotoxemia and acute cutaneous anaphylaxis, suggesting that SHIP1 agonists could be used therapeutically to inhibit the PI3K pathway.

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