scholarly journals The Novel Phosphatidylinositol-3-Kinase (PI3K) Inhibitor Alpelisib Effectively Inhibits Growth of PTEN-Haploinsufficient Lipoma Cells

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1586 ◽  
Author(s):  
Anna S. Kirstein ◽  
Adrien Augustin ◽  
Melanie Penke ◽  
Michele Cea ◽  
Antje Körner ◽  
...  
Keyword(s):  
Cell Death ◽  
Adipocyte Differentiation ◽  
Suppressor Gene ◽  
Pi3k Inhibitor ◽  
Dependent Manner ◽  
The Novel ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Phosphorylation ◽  
Ribosomal Protein S6 ◽  
New Treatment

Germline mutations in the tumor suppressor gene PTEN cause PTEN Hamartoma Tumor Syndrome (PHTS). Pediatric patients with PHTS frequently develop lipomas. Treatment attempts with the mTORC1 inhibitor rapamycin were unable to reverse lipoma growth. Recently, lipomas associated with PIK3CA-related overgrowth syndrome were successfully treated with the novel PI3K inhibitor alpelisib. Here, we tested whether alpelisib has growth-restrictive effects and induces cell death in lipoma cells. We used PTEN-haploinsufficient lipoma cells from three patients and treated them with alpelisib alone or in combination with rapamycin. We tested the effect of alpelisib on viability, proliferation, cell death, induction of senescence, adipocyte differentiation, and signaling at 1–100 µM alpelisib. Alpelisib alone or in combination with rapamycin reduced proliferation in a concentration- and time-dependent manner. No cell death but an induction of senescence was detected after alpelisib incubation for 72 h. Alpelisib treatment led to a reduced phosphorylation of AKT, mTOR, and ribosomal protein S6. Rapamycin treatment alone led to increased AKT phosphorylation. This effect could be reversed by combining rapamycin with alpelisib. Alpelisib reduced the size of lipoma spheroids by attenuating adipocyte differentiation. Since alpelisib was well tolerated in first clinical trials, this drug alone or in combination with rapamycin is a potential new treatment option for PHTS-related adipose tissue overgrowth.

scholarly journals Cross-Talk between Phosphatidylinositol 3-Kinase/AKT and c-Jun NH2-Terminal Kinase Mediates Survival of Isolated Human Islets

Endocrinology ◽  
2004 ◽  
Vol 145 (10) ◽  
pp. 4522-4531 ◽  
Author(s):  
Reid Aikin ◽  
Dusica Maysinger ◽  
Lawrence Rosenberg
Keyword(s):  
Cell Death ◽  
Cross Talk ◽  
Specific Cell ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Activation ◽  
And Function ◽  
Jnk Activation ◽  
Islet Survival ◽  
Phosphatidylinositol 3

Abstract Therapeutic strategies aimed at the inhibition of specific cell death mechanisms may increase islet yield and improve cell viability and function after routine isolation. The aim of the current study was to explore the possibility of AKT-JNK cross-talk in islets after isolation and the relevance of c-jun NH2-terminal kinases (JNK) suppression on islet survival. After routine isolation, increased AKT activity correlated with suppression of JNK activation, suggesting that they may be related events. Indeed, the increase in AKT activation after isolation correlated with suppression of apoptosis signal-regulating kinase 1 (ASK1), a kinase acting upstream of JNK, by phosphorylation at Ser83. We therefore examined whether modulators of phosphatidylinositol 3-kinase (PI3K)/AKT signaling affected JNK activation. PI3K inhibition led to increased JNK phosphorylation and islet cell death, which could be reversed by the specific JNK inhibitor SP600125. In addition, IGF-I suppressed cytokine-mediated JNK activation in a PI3K-dependent manner. We also demonstrate that inhibition of PI3K rendered islets more susceptible to cytokine-mediated cell death. SP600125 transiently protected islets from cytokine-mediated cell death, suggesting that JNK may not be necessary for cytokine-induced cell death. When administered immediately after isolation, SP600125 improved islet survival and function, even 48 h after removal of SP600125, suggesting that JNK inhibition by SP600125 may be a viable strategy for improving isolated islet survival. Taken together, these results demonstrate that PI3K/AKT suppresses the JNK pathway in islets, and this cross-talk represents an important antiapoptotic consequence of PI3K/AKT activation.

scholarly journals The PI3K/Akt pathway is involved in early infection of some exogenous avian leukosis viruses

2011 ◽  
Vol 92 (7) ◽  
pp. 1688-1697 ◽  
Author(s):  
Shao-zhen Feng ◽  
Wei-sheng Cao ◽  
Ming Liao
Keyword(s):  
Viral Entry ◽  
Early Stage ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Phosphorylation ◽  
Akt Activation ◽  
Pi3k Inhibitors ◽  
Cellular Factors ◽  
Dose Dependent

Avian leukosis virus (ALV) is an enveloped and oncogenic retrovirus. Avian leukosis caused by the members of ALV subgroups A, B and J has become one of the major problems challenging the poultry industry in China. However, the cellular factors such as signal transduction pathways involved in ALV infection are not well defined. In this study, our data demonstrated that ALV-J strain NX0101 infection in primary chicken embryo fibroblasts or DF-1 cells was correlated with the activity and phosphorylation of Akt. Akt activation was initiated at a very early stage of infection independently of NX0101 replication. The specific phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 or wortmannin could suppress Akt phosphorylation, indicating that NX0101-induced Akt phosphorylation is PI3K-dependent. ALV-A strain GD08 or ALV-B strain CD08 infection also demonstrated a similar profile of PI3K/Akt activation. Treatment of DF-1 cells with the drug 5-(N, N-hexamethylene) amiloride that inhibits the activity of chicken Na+/H+ exchanger type 1 significantly reduced Akt activation induced by NX0101, but not by GD08 and CD08. Akt activation triggered by GD08 or CD08 was abolished by clathrin-mediated endocytosis inhibitor chlorpromazine. Receptor-mediated endocytosis inhibitor dansylcadaverine had a negligible effect on all ALV-induced Akt phosphorylation. Moreover, viral replication of ALV was suppressed by LY294002 in a dose-dependent manner, which was due to the inhibition of virus infection by LY294002. These data suggest that the activation of the PI3K/Akt signalling pathway by exogenous ALV infection plays an important role in viral entry, yet the precise mechanism remains under further investigation.

scholarly journals MINK1 modulates 5FU resistance in OSCC through AKT/MDM2 mediated regulation of p53

2021 ◽  
Author(s):  
Sibasish Mohanty ◽  
Pallavi Mohapatra ◽  
Omprakash Shriwas ◽  
Manashi Priyadarshini ◽  
Shamima Azma Ansari ◽  
...  
Keyword(s):  
Cell Death ◽  
Clinical Investigation ◽  
Tumor Burden ◽  
Negative Regulator ◽  
Clinical Samples ◽  
The Novel ◽  
Akt Phosphorylation ◽  
Tumor Tissues ◽  
Patients Experience

Cisplatin, 5FU and docetaxel (TPF) are the most common chemotherapy regimen used for advanced OSCC. However, many cancer patients experience relapse, continued tumor growth, and spread due to drug resistance, which leads to treatment failure and metastatic disease. Here, using a CRISPR/Cas9 based kinome knockout screening, Misshapen-like kinase 1 (MINK1) is identified as an important mediator of 5FU resistance in OSCC. Analysis of clinical samples demonstrated significantly higher MINK1 expression in the tumor tissues of chemotherapy non-responder as compared to chemotherapy responders. The in-vitro and xenograft experiments indicate that knocking out MINK1 restores 5FU mediated cell death in chemoresistant OSCC. An antibody based phosphorylation array screen revealed MINK1 as a negative regulator of p53. Mechanistically, MINK1 modulates AKT phosphorylation at Ser473, which enables p-MDM2 (Ser 166) mediated degradation of p53. We also identified lestaurtinib as a potent inhibitor of MINK1 kinase activity. Lestaurtinib significantly induces 5FU mediated cell death in chemoresistant OSCC lines. The patient derived chemoresistant cell based xenograft data suggest that lestaurtinib restores 5FU sensitivity and facilitates a significant reduction of tumor burden. Overall, our study suggests that MINK1 is a major driver of 5FU resistance in OSCC. The novel combination of MINK1 inhibitor lestaurtinib and 5FU needs further clinical investigation in advanced OSCC.

scholarly journals UVB-Induced Nuclear Translocation of PTEN Promotes Radiation Sensitivity of Human Malignant Glioma U87MG Cells

2020 ◽  
Author(s):  
Wei Zhao ◽  
Chao Yao ◽  
Yang An ◽  
Yuting Jia ◽  
Zhenhua Song ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Uv Irradiation ◽  
Nuclear Translocation ◽  
Radiation Sensitivity ◽  
Suppressor Gene ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Pi3k Signaling Pathway ◽  
The Relationship

Abstract BackgroundPTEN is a tumor suppressor gene, which is often inactivated through mutation and/or deletion in diverse human tumors. In the cytoplasm, PTEN negatively regulates the phosphatidylinositol 3′ kinase (PI3K) signaling pathway, while PTEN also shuttles to the nucleus, where PTEN stabilizes genome and/or participates in DNA repairment after damage. PTEN’s subcellular localization seems to be regulated by various factors. MethodsU87MG cells with expressing Wild-type-PTEN (WT-PTEN) and K13E-PTEN mutant were engineered respectively. The relationship between UV radiation and PTEN’s subcellular localization were elucidated using nuclear and cytosolic fractionation and fluorescence co-localization assay. Related signaling pathways were studied with western blot assays.ResultsHere, we demonstrated that UV irradiation could promote nuclear translocation of both WT-PTEN and K13E-PTEN mutant in a dose-dependent manner, but WT PTEN had a higher level of nuclear accumulation after inducing by UV-irradiation compared to K13E-PTEN. In contrast, the cytoplasmic-nuclear translocation of exogenous PTEN was critical to its tumor-suppressing functions that made U87MG cells more sensitive to the UV irradiation. ConclusionOur findings may have implications for further revealing the function of nuclear PTEN and provide insights for clinical treatment of PTEN-deficient tumors.

scholarly journals 20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism

2009 ◽  
Vol 297 (3) ◽  
pp. F662-F670 ◽  
Author(s):  
Talha Akbulut ◽  
Kevin R. Regner ◽  
Richard J. Roman ◽  
Ellis D. Avner ◽  
John R. Falck ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Dienoic Acid ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Renal Epithelial Cells ◽  
Akt Phosphorylation ◽  
Src Inhibitor ◽  
Epidermal Growth

20-Hydroxyeicosatetraenoic acid (20-HETE) has been reported to promote mitogenicity in a variety of cell types, including renal epithelial cells. However, the signal transduction pathways activated by 20-HETE have not been fully defined. The present study evaluated the effects of 20-HETE and its more stable agonist analogs 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (5,14-20-HEDE) and N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-20-HEDGE) on the Raf/MEK/ERK and phosphatidylinositol 3-kinase (PI3K)-Akt pathway in LLC-PK1 renal epithelial cells. 20-HETE (20 μM) increased phosphorylation of Raf-1 (2.5 ± 0.2-fold), MEK1/2 (6.3 ± 1.6-fold), and ERK1/2 (5.8 ± 0.3-fold) compared with vehicle-treated cells. Similarly, the 20-HETE analogs also strongly activated ERK1/2 in a Raf-1- and MEK1/2-dependent manner. Moreover, 5,14-20-HEDE increased Akt phosphorylation by 2.2 ± 0.3-fold. 20-HETE and 5,14-20-HEDE also promoted activation (Y1086) of epidermal growth factor receptor (EGFR; Y1086) by 1.9 ± 0.2- and 2.5 ± 0.2-fold, respectively. These effects were completely blocked by the EGFR inhibitor EKB-569 (0.1 μM). Moreover, EKB-569 (0.1 μM), as well as a c-Src inhibitor, SKI-606 (0.05 μM), completely abolished the 20-HETE-mediated activation of the Raf/MEK/ERK and PI3K-Akt pathways. Blockade of PKC with bisindolylmaleimide I had no effect on 20-HETE-induced ERK1/2 activation. This study demonstrated that 20-HETE activated the Raf/MEK/ERK and Akt pathways in renal epithelial cells secondary to the activation of c-Src and EGFR.

scholarly journals Ceramide-induced cell death/survival in murine osteoblasts

2010 ◽  
Vol 206 (2) ◽  
pp. 225-233 ◽  
Author(s):  
P A Hill ◽  
A Tumber
Keyword(s):  
Cell Death ◽  
Cell Viability ◽  
Cell Types ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Pi3k Inhibitors ◽  
Diphenyl Tetrazolium Bromide ◽  
General Protein ◽  
Pkc Ζ ◽  
Cell Suicide

Programmed cell death (PCD) or apoptosis is a naturally occurring cell suicide pathway induced in a variety of cell types. We determined whether ceramide treatment contributes to reduced cell viability and increased PCD in primary osteoblasts and the signalling pathways that are involved. Cell viability was determined by the 3-(4,5-dimethyl-thiozol-2-yl)-2,5-diphenyl tetrazolium bromide assay. We found that C2-ceramide (≤10−7 M) promoted osteoblast viability, whilst concentrations ≥2×10−6 M significantly reduced osteoblast viability in a dose- and time-dependent manner. The effect of ceramide on cell viability was specific since C2-dihydroceramide had no effect. Increasing intracellular ceramide levels with either sphingomyelinase (SMase) or an inhibitor of ceramide metabolism also increased osteoblast apoptosis. Ceramide-induced PCD in osteoblasts was determined by nuclear appearance and DNA fragmentation. PCD was induced by both C2-ceramide and SMase. The ability of ceramide (5×10−8 M) to promote osteoblast survival was prevented by a general protein kinase C (PKC) inhibitor and by a PKC ζ inhibitor, whilst osteoblast survival was enhanced in the presence of a protein phosphatase 1 (PP1) inhibitor. Phosphatidylinositol-3 kinase (PI3K) inhibitors had no effect on osteoblast survival. The ability of ceramide (5×10−5 M) to induce apoptosis was prevented by the inhibitors of PP1 and PKC δ, whilst the general PKC and PI3K inhibitors had no effect on it. Our findings suggest that ceramide signals osteoblast survival and apoptosis through different intracellular pathways, and that alteration in the intracellular levels of ceramide may play an important role in bone remodelling.

scholarly journals PTEN affects cell size, cell proliferation and apoptosis during Drosophila eye development

Development ◽  
1999 ◽  
Vol 126 (23) ◽  
pp. 5365-5372 ◽  
Author(s):  
H. Huang ◽  
C.J. Potter ◽  
W. Tao ◽  
D.M. Li ◽  
W. Brogiolo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Cell Size ◽  
Insulin Signaling ◽  
Cell Cycle Progression ◽  
Eye Development ◽  
Suppressor Gene ◽  
Pten Gene ◽  
Dependent Manner ◽  
Culture Cells

Mutations in the tumor suppressor gene PTEN (MMAC1/TEP1) are associated with a large number of human cancers and several autosomal-dominant disorders. Mice mutant for PTEN die at early embryonic stages and the mutant embryonic fibroblasts display decreased sensitivity to cell death. Overexpression of PTEN in different mammalian tissue culture cells affects various processes including cell proliferation, cell death and cell migration. We have characterized the Drosophila PTEN gene and present evidence that both inactivation and overexpression of PTEN affect cell size, while overexpression of PTEN also inhibits cell cycle progression at early mitosis and promotes cell death during eye development in a context-dependent manner. Furthermore, we have shown that PTEN acts in the insulin signaling pathway and all signals from the insulin receptor can be antagonized by either Drosophila or human PTEN, suggesting a potential means for alleviating symptoms associated with altered insulin signaling.

scholarly journals Selective abrogation of S6K2 maps lipid homeostasis as a survival vulnerability in MAPKi-resistant NRASmut melanoma

2021 ◽  
Author(s):  
Hsin-Yi Chen ◽  
Aaron R. Goldman ◽  
Delaine Zayas-Bazan ◽  
Patricia I. Reyes-Uribe ◽  
Adam N. Guterres ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Fatty Acids ◽  
Cell Death ◽  
Fatty Acid ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Lipid Homeostasis ◽  
Dependent Manner ◽  
S6 Kinase ◽  
Ribosomal Protein S6

Although oncogenic NRAS activates MAPK signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS-mutant tumors. Here we report that silencing the ribosomal protein S6 kinase 2 (S6K2), while preserving the activity of S6K1, perturbs lipid metabolism, enhances fatty acid unsaturation, triggers lipid peroxidation and induces cell death selectively in NRAS-mutant melanoma cells that are resistant to MAPK inhibition. S6K2 depletion stimulates SREBP1 activity in an S6K1-dependent manner and relieves suppression of PPARα, triggering apoptosis and ferroptosis. Combining PPARα agonists and polyunsaturated fatty acids phenocopies the effects of S6K2 abrogation, blocking tumor growth. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for NRAS-mutant melanoma that are resistant to global MAPK pathway inhibitors.

scholarly journals Nicorandil Protects the Heart from Ischemia/Reperfusion Injury by Attenuating Endoplasmic Reticulum Response-induced Apoptosis Through PI3K/Akt Signaling Pathway

2015 ◽  
Vol 35 (6) ◽  
pp. 2320-2332 ◽  
Author(s):  
Hui Wu ◽  
Ming Ye ◽  
Jun Yang ◽  
Jiawang Ding ◽  
Jian Yang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Infarct Size ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Pi3k Inhibitor ◽  
Myocardial Infarct Size ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Induced Apoptosis ◽  
Phosphatidylinositol 3

Background/Aims: As a vasodilatory drug used to treat angina, nicorandil has been shown to induce an infarct-limiting effect in various experimental animal models of myocardial ischemia-reperfusion (IR). There are multiple mechanisms causing the IR injury, among which, the endoplasmic reticulum (ER) stress and ER stress-initiated apoptosis are implicated to play an important role. However, whether ER stress is involved in nicorandil-induced cardioprotection is unknown. Methods: Post-ischemic functional recovery, lactate dehydrogenase (LDH) release and infarct size in perfused rat hearts subjected to global no-flow I/R were measured to analysis the effect of nicorandil and ER stress inducer of tunicamycin as well as phosphatidylinositol 3-kinase (PI3K) inhibitor of wortmannin on the I/R hearts. The I/R hearts tissue were harvested to evaluate apoptosis ratio with TUNEL assay and protein expression with western blot. Results: We showed that nicorandil ameliorated postischemic contractile recovery, as well as significantly reduced myocardial infarct size at a dose-dependent manner. Furthermore, nicorandil treatment inhibited the IR-induced apoptosis and ER stress. The beneficial effects of nicorandil were blocked by ER stress inducer, tunicamycin and specific phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Concolusion: We conclude that the cardioprotection of nicorandil was at least in part mediated via inhibition of ER stress-induced apoptotic cell death through PI3K/Akt pathway.

PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia

2009 ◽  
Vol 296 (4) ◽  
pp. F847-F858 ◽  
Author(s):  
Kurinji Singaravelu ◽  
Kishor Devalaraja-Narashimha ◽  
Brynn Lastovica ◽  
Babu J. Padanilam
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Suppressor Gene ◽  
Apoptotic Cell Death ◽  
Renal Ischemia ◽  
Dependent Manner ◽  
Apoptotic Pathways

The p53 tumor suppressor gene plays a crucial role in mediating apoptotic cell death in renal ischemia-reperfusion injury (IRI). To further elucidate the p53-dependent pathway, we investigated the role of the p53 apoptosis effector related to PMP-22 (PERP), an apoptosis-associated p53 transcriptional target. PERP mRNA and protein are highly induced in the outer medullary proximal tubular cells (PTC) of ischemic kidneys postreperfusion at 3, 12, and 24 h in a p53-dependent manner. In PTC, overexpression of PERP augmented the rate of apoptosis following hypoxia by inducing mitochondrial permeability and subsequent release of cytochrome c, apoptosis-inducing factor (AIF), and caspase 9 activation. In addition, silencing of the PERP gene with short hairpin RNA prevented apoptosis in hypoxia-mediated injury by precluding mitochondrial dysfunction and consequent cytochrome c and AIF translocation. These data suggest that PERP is a key effector of p53-mediated apoptotic pathways and is a potential therapeutic target for renal IRI.

Sign in / Sign up

Export Citation Format

Share Document