scholarly journals The Protective Effect of Early Hypothermia on PTEN Phosphorylation Correlates with Free Radical Inhibition in Rat Stroke

2009 ◽  
Vol 29 (9) ◽  
pp. 1589-1600 ◽  
Author(s):  
Sang Mi Lee ◽  
Heng Zhao ◽  
Carolina M Maier ◽  
Gary K Steinberg
Keyword(s):  
Protective Effect ◽  
Artery Occlusion ◽  
Akt Pathway ◽  
Moderate Hypothermia ◽  
Ischemic Damage ◽  
Protective Mechanisms ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Phosphorylated Akt ◽  
Transient Focal Ischemia

We recently showed that intraischemic moderate hypothermia (30°C) reduces ischemic damage through the Akt pathway after permanent distal middle cerebral artery occlusion in rats. The only Akt pathway component preserved by hypothermia is phosphorylated phosphatase and tensin homolog deleted on chromosome 10 (p-PTEN), which suggests that p-PTEN may have a central role in neuroprotection. Reactive oxygen species (ROS) are critically involved in mediating ischemic damage after stroke by interacting with signaling molecules, including Akt, PTEN, and δ-protein kinase C (PKC). We investigated the protective mechanisms of moderate hypothermia on these signaling proteins after transient focal ischemia in rats. Early moderate hypothermia (3h) was administered 15 mins before reperfusion, and delayed moderate hypothermia (3h) was applied 15 mins after reperfusion. Our results indicate that early hypothermia reduced infarction, whereas delayed hypothermia did not. However, both early and delayed hypothermia maintained levels of Mn-SOD (superoxide dismutase) and phosphorylated Akt and blocked δ-PKC cleavage, suggesting that these factors may not be critical to the protection of hypothermia. Nevertheless, early hypothermia preserved p-PTEN levels after reperfusion, whereas delayed hypothermia did not. Furthermore, ROS inhibition maintained levels of p-PTEN after stroke. Together, these findings suggest that phosphorylation levels of PTEN are closely associated with the protective effect of early hypothermia against stroke.

LINC00893 inhibits papillary thyroid cancer by suppressing AKT pathway via stabilizing PTEN

2020 ◽  
pp. 1-10
Author(s):  
Shujing Li ◽  
Yanyan Zhang ◽  
Jian Dong ◽  
Ruihuan Li ◽  
Bo Yu ◽  
...  
Keyword(s):  
Akt Pathway ◽  
Phosphatase And Tensin Homolog ◽  
Fused In Sarcoma ◽  
Tensin Homolog ◽  
Phosphorylated Akt ◽  
Pten Mrna ◽  
Non Coding Rnas ◽  
And Migration ◽  
Fus Protein ◽  
Proliferation And Migration

Long non-coding RNAs (lncRNAs) are important to the occurrence and advancement of human cancers. We found through GEPIA that LINC00893 was lowly expressed in thyroid carcinoma (THCA) tissues, whereas the specific functions of LINC00893 has never been reported in PTC. In the current study, we confirmed that LINC00893 was expressed at a low level in PTC cells. Through gain-of-function assays, we determined that LINC00893 overexpression abrogated proliferation and migration abilities of PTC cells. Through signal transduction reporter array we found that LINC00893 potentially modulated the signals of phosphatase and tensin homolog (PTEN)/AKT pathway. In addition, overexpression of LINC00893 increased the expression of PTEN but reduced the levels of phosphorylated AKT in PTC. Additionally, mechanism assays unveiled that LINC00893 stabilized PTEN mRNA via recruiting Fused in sarcoma (FUS) protein. Finally, rescue assays demonstrated that LINC00893 hampered the proliferation and migration of PTC cells via PTEN/AKT pathway. Together, our study first clarified that LINC00893 functions as a tumor suppressor in PTC by blocking AKT pathway through PTEN upregulation.

scholarly journals An Immunohistochemical Study of the PTEN/AKT Pathway Involvement in Canine and Feline Mammary Tumors

Animals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 365
Author(s):  
Pietro Asproni ◽  
Francesca Millanta ◽  
Lorenzo Ressel ◽  
Fabio Podestà ◽  
Francesca Parisi ◽  
...  
Keyword(s):  
Immunohistochemical Study ◽  
Lymphatic Invasion ◽  
Pten Expression ◽  
Akt Pathway ◽  
Phosphatase And Tensin Homolog ◽  
Mammary Carcinomas ◽  
Tensin Homolog ◽  
Aggressive Tumors ◽  
Aggressive Subtype ◽  
Viral Oncogene Homolog

Phosphatase and tensin homolog deleted on chromosome10 (PTEN), phospho-v-Akt murine thymoma viral oncogene homolog (AKT), and the Rapamycin-Insensitive Companion of mTOR (Rictor) expression was investigated by immunohistochemistry in 10 canine mammary adenomas (CMAs), 40 canine mammary carcinomas (CMCs), and 30 feline mammary carcinomas (FMCs). All the CMAs, 25 of 40 CMCs (63%) and 7 of 30 FMCs (23%), were PTEN-positive. In dogs, no CMAs and 15 of 25 CMCs (37%) expressed phospho-AKT (p-AKT), while 24 of 30 FMCs (82%) were p-AKT-positive. One of 10 CMAs (10%), 24 of 40 CMCs (60%) and 20 of 30 FMCs (67%) were Rictor-positive. In the dog, PTEN expression correlated with less aggressive tumors, absence of lymphatic invasion, and longer survival. P-AKT expression correlated with more aggressive subtype, lymphatic invasion, and poorer survival and Rictor expression with lymphatic invasion. In cats, PTEN correlated with less aggressive carcinomas, absence of lymphatic invasion, and better survival. P-AKT and Rictor expression correlated with poorer survival. PTEN expression was inversely correlated with p-AKT and Rictor in both species, while p-AKT positively correlated with Rictor expression. A strong PTEN/AKT pathway involvement in behavior worsening of CMT and FMTs is demonstrated, providing a rationale for further studies of this pathway in veterinary oncology.

scholarly journals Curcumin regulates the miR-21/PTEN/Akt pathway and acts in synergy with PD98059 to induce apoptosis of human gastric cancer MGC-803 cells

2019 ◽  
Vol 47 (3) ◽  
pp. 1288-1297 ◽  
Author(s):  
Zhanrong Qiang ◽  
Lingyu Meng ◽  
Caixia Yi ◽  
Lianying Yu ◽  
Wenxia Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Mitogen Activated Protein Kinase ◽  
Cell Counting ◽  
Akt Pathway ◽  
High Dose ◽  
Human Gastric Cancer ◽  
Dependent Manner ◽  
Tensin Homolog ◽  
Phosphorylated Akt ◽  
Mitogen Activated Protein

Objective PD98059 is a potent and selective inhibitor of mitogen-activated protein kinase. Substantial preclinical evidence has shown an anti-tumor effect of curcumin on various solid tumors. This study aimed to investigate whether curcumin synergistically acts with PD98059 in exerting anti-gastric cancer effects. Methods The cell counting kit-8 assay was used to detect cell proliferation of the human gastric cancer MGC-803 cell line. Flow cytometry was performed to detect apoptosis. Western blotting was used to detect phosphatase and tensin homolog (PTEN) and phosphorylated Akt (p-Akt) expression levels. Quantitative reverse transcription-polymerase chain reaction was used to determine microRNA-21 (miR-21). Results A dose of 5 to 40 µM curcumin inhibited proliferation of MGC-803 cells in a dose- and time-dependent manner. A high dose of curcumin strongly inhibited p-Akt protein expression. With increasing curcumin levels, PTEN expression increased and miR-21 levels decreased. These results suggest that curcumin negatively modulated the miR-21/PTEN/Akt pathway. Moreover, after pretreatment with PD98059, cell apoptosis induced by curcumin was significantly increased. Additionally, the inhibitory effects of curcumin on the miR-21/PTEN/Akt pathway were significantly enhanced. Conclusion PD98059 combined with curcumin may be a potential strategy for managing gastric cancer.

scholarly journals HES1 opposes a PTEN-dependent check on survival, differentiation, and proliferation of TCRβ-selected mouse thymocytes

Blood ◽  
2012 ◽  
Vol 120 (7) ◽  
pp. 1439-1448 ◽  
Author(s):  
Gladys W. Wong ◽  
Gisele C. Knowles ◽  
Tak W. Mak ◽  
Adolfo A. Ferrando ◽  
Juan Carlos Zúñiga-Pflücker
Keyword(s):  
T Cell ◽  
Notch Signaling ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Akt Pathway ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Developmental Progression ◽  
Differentiation And Proliferation ◽  
Immature Thymocytes

Abstract The developmental progression of immature thymocytes requires cooperative input from several pathways, with Notch signals playing an indispensable role at the T-cell receptor (TCR)–β selection checkpoint. Notch signals affect the activation of the PI3K/Akt pathway, which is required for pTα/TCRβ (pre-TCR)–induced survival, differentiation, and proliferation of developing αβ-lineage thymocytes. However, the molecular players responsible for the interaction between the Notch and PI3K pathways at this critical developmental stage are unknown. Here, we show that Notch induction of Hes1 is necessary to repress the PI3K/Akt pathway inhibitor, PTEN (phosphatase and tensin homolog), which in turn facilitates pre-TCR–induced differentiation. In support of this mechanism, deletion or down-regulation of Pten overcomes the Notch signaling requirement for survival and differentiation during β-selection. In addition, c-Myc is a critical target of Notch at this stage, as c-Myc expression overcomes the Notch signaling requirement for proliferation during β-selection. Collectively, our results point to HES1, via repression of PTEN, and c-Myc as critical mediators of Notch function at the β-selection checkpoint.

scholarly journals The Major Target of the Endogenously Generated Reactive Oxygen Species in Response to Insulin Stimulation Is Phosphatase and Tensin Homolog and Not Phosphoinositide-3 Kinase (PI-3 Kinase) in the PI-3 Kinase/Akt Pathway

2005 ◽  
Vol 16 (1) ◽  
pp. 348-357 ◽  
Author(s):  
Ji Hae Seo ◽  
Younghee Ahn ◽  
Seung-Rock Lee ◽  
Chang Yeol Yeo ◽  
Kyu Chung Hur
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Lines ◽  
Membrane Fraction ◽  
Akt Pathway ◽  
Oxygen Species ◽  
Insulin Stimulation ◽  
Phosphatase And Tensin Homolog ◽  
Downstream Signaling ◽  
Tensin Homolog ◽  
Phosphoinositide 3 Kinase

Phosphoinositide-3 kinase (PI-3 kinase) and its downstream signaling molecules PDK-1 and Akt were analyzed in SK-N-SH and SK-N-BE(2) human neuroblastoma cell lines. When cells were stimulated with insulin, PI-3 kinase was activated in both cell lines, whereas the translocation of PDK-1 to the membrane fraction and phosphorylated Akt were observed only in SK-N-SH cells. Analyses of the insulin-mediated reactive oxygen species (ROS) generation and Phosphatase and Tensin homolog (PTEN) oxidation indicate that PTEN oxidation occurred in SK-N-SH cells, which can produce ROS, but not in SK-N-BE(2) cells, which cannot increase ROS in response to insulin stimulation. When SK-N-SH cells were pretreated with the NADPH oxidase inhibitor diphenyleneiodonium chloride before insulin stimulation, insulin-mediated translocation of PDK-1 to the membrane fraction and phosphorylation of Akt were remarkably reduced, whereas PI-3 kinase activity was not changed significantly. These results indicate that not only PI-3 kinase activation but also inhibition of PTEN by ROS is needed to increase cellular level of phosphatidylinositol 3,4,5-trisphosphate for recruiting downstream signaling molecules such as PDK-1 and Akt in insulin-mediated signaling. Moreover, the ROS generated by insulin stimulation mainly contributes to the inactivation of PTEN and not to the activation of PI-3 kinase in the PI-3 kinase/Akt pathway.

Inhibition of the RKIP and PTEN-Transcription Repressor Snail in B-NHL by the Proteasome Inhibitor NPI-0052: Roles of RKIP and PTEN Induction in the Reversal of Resistance to TRAIL Apoptosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3938-3938
Author(s):  
Stavroula Baritaki ◽  
Kam Yeung ◽  
Katherine Wu ◽  
Haiming Chen ◽  
James R. Berenson ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Proteasome Inhibitors ◽  
Akt Pathway ◽  
Gene Products ◽  
Direct Role ◽  
Phosphatase And Tensin Homolog ◽  
Apoptotic Gene ◽  
Tensin Homolog ◽  
Survival Pathways

Abstract Abstract 3938 Poster Board III-874 Several strategies have been examined to reverse tumor cell resistance to immunotherapy. For instance, proteasome inhibitors such as Bortezomib, MG-132 and NPI-0052 have been reported to sensitize hematopoietic tumor cells to TRAIL-mediated apoptosis. NPI-0052 mediates its cytotoxic and sensitizing effects in lymphoma cells through the inhibition of the NF-κB and PI3K/Akt survival pathways. The molecular mechanisms and associated gene products involved in NPI-0052-induced inhibition of these pathways are not known. We have reported that NPI-0052 induced the expression of Raf-1 kinase inhibitor protein (RKIP) via inhibition of NF-κB activity and downstream the RKIP transcription repressor Snail (Baritaki et al., Oncogene. 2009, PMID: 19633685). Also, Snail has been reported to repress phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and allowing the Akt pathway to remain activated. Based on these findings, we hypothesized that treatment of B-NHL cells with NPI-0052 will result in the induction of both RKIP and PTEN through inhibition of Snail and, consequently, will result in the inhibition of the NF-κB and Akt pathways, respectively. Treatment of Ramos cells with NPI-0052 resulted in the inhibition of NF-κB activity and Snail expression along with the induction of both RKIP and PTEN expression, as assessed by western. The direct roles of RKIP and PTEN in B-NHL cell sensitization to TRAIL were demonstrated by the use of cells transfected with siRNA RKIP and siRNA PTEN, whereby reversal of sensitivity occurred. In contrast, Snail knockdown by siRNA Snail resensitized the cells to TRAIL apoptosis. The inhibition by NPI-0052 of both the NF-κB and PI3K/Akt pathways resulted downstream in the inhibition of transcription and/or activity of anti-apoptotic gene products such as Bcl-2 family members. The direct role of Bcl-2 family anti-apoptotic gene products in the reversal of resistance by NPI-0052 was demonstrated by the use of the Bcl-2 family chemical inhibitor 2MAM3. Altogether, these findings demonstrate that NPI-0052 modifies a tightly regulated loop in the resistance of B-NHL cells, namely, the constitutive activation of NF-κB and Akt survival pathways that crosstalk and induce Snail. Snail in turn, represses RKIP and PTEN and, thus, the cells continue to survive and proliferate. However, upon treatment with NPI-0052, the inhibition of PI3K/Akt and NF-κB activities results downstream in the inhibition of Snail and the inhibition of Snail, in turn, derepresses the transcription of both RKIP and PTEN. In a feedback loop, the induction of RKIP represses the NF-κB pathway and the induction of PTEN represses the PI3K/Akt pathway. Hence, the inhibition by NPI-0052 of the NF-κB/Akt/Snail/RKIP/PTEN regulatory resistance loop in B-NHL cells results in the reversal of resistance. Further, these findings identify several new targets for potential therapeutic intervention in the reversal of resistance. Disclosures: Berenson: Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Palladino:Nereus Pharmaceuticals: Employment, Equity Ownership.

Conditions of protection by hypothermia and effects on apoptotic pathways in a rat model of permanent middle cerebral artery occlusion

2007 ◽  
Vol 107 (3) ◽  
pp. 636-641 ◽  
Author(s):  
Heng Zhao ◽  
Jade Q. Wang ◽  
Takayoshi Shimohata ◽  
Guohua Sun ◽  
Midori A. Yenari ◽  
...  
Keyword(s):  
Infarct Size ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Mild Hypothermia ◽  
Artery Occlusion ◽  
Moderate Hypothermia ◽  
Ischemic Damage ◽  
Mca Occlusion ◽  
Apoptotic Pathways ◽  
Collateral Vessels

Object Hypothermia is protective in stroke models, but findings from permanent occlusion models are conflicting. In this article the authors induced focal ischemia in rats by permanent distal middle cerebral artery (MCA) occlusion plus transient occlusion of the common carotid arteries (CCAs). This models a scenario in which the MCA remains occluded but partial reperfusion occurs through collateral vessels. The authors also determined whether hypothermia mediates ischemic damage by blocking apoptotic pathways. Methods The left MCA was occluded permanently and the CCAs were reopened after 2 hours, leading to partial reperfusion in rats maintained at 37°C, 33°C (mild hypothermia), or 30°C (moderate hypothermia) for 2 hours during and/or after CCA occlusion (that is, for a total of 2 or 4 hours of hypothermia or normothermia). Infarct size was measured 2 days after the stroke. Immunofluorescence staining and Western blot analysis were used to detect cytochrome c and apoptosis inducing factor (AIF) translocation. Results Four hours of prolonged mild hypothermia (33°C) reduced the infarct size 22% in the model of permanent MCA occlusion, whereas 2 hours of such mild hypothermia maintained either during CCA occlusion or after CCA release did not attenuate ischemic damage. However, moderate hypothermia (30°C) during CCA occlusion was significantly more protective than 4 hours of 33°C (46% decrease in infarct size). Four hours of mild or moderate hypothermia reduced cytosolic cytochrome c release and both nuclear and cytosolic AIF translocation in the penumbra 2 days after stroke. Conclusions These findings suggest that hypothermic neuroprotection might be achieved by blocking AIF and cytochrome c–mediated apoptosis.

scholarly journals PTEN Activation by DNA Damage Induces Protective Autophagy in Response to Cucurbitacin B in Hepatocellular Carcinoma Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Yanan Niu ◽  
Wen Sun ◽  
Jin-Jian Lu ◽  
Dik-Lung Ma ◽  
Chung-Hang Leung ◽  
...  
Keyword(s):  
Dna Damage ◽  
Carcinoma Cells ◽  
Caspase Activation ◽  
Phosphatase And Tensin Homolog ◽  
Cucurbitacin B ◽  
Tensin Homolog ◽  
Phosphorylated Akt ◽  
Protein Expressions ◽  
Ros Formation ◽  
Induced Apoptosis

Cucurbitacin B (Cuc B), a natural product, induced both protective autophagy and DNA damage mediated by ROS while the detailed mechanisms remain unclear. This study explored the mechanism of Cuc B-induced DNA damage and autophagy. Cuc B decreased cell viability in concentration- and time-dependent manners. Cuc B caused long comet tails and increased expression of γ-H2AX, phosphorylation of ATM/ATR, and Chk1/Chk2. Cuc B induced autophagy as evidenced by monodansylcadaverine (MDC) staining, increased expression of LC3II, phosphorylated ULK1, and decreased expression of phosphorylated AKT, mTOR. Cuc B induced apoptosis mediated by Bcl-2 family proteins and caspase activation. Furthermore, Cuc B induced ROS formation, which was inhibited by N-acetyl-L-cysteine (NAC). NAC pretreatment dramatically reversed Cuc B-induced DNA damage, autophagy, and apoptosis. Cuc B-induced apoptosis was reversed by NAC but enhanced by 3-methyladenine (3-MA), chloroquine (CQ), and silencing phosphatase and tensin homolog (PTEN). 3-MA and CQ showed no effect on Cuc B-induced DNA damage. In addition, Cuc B increased PTEN phosphorylation and silence PTEN restored Cuc B-induced autophagic protein expressions without affecting DNA damage. In summary, Cuc B induced DNA damage, apoptosis, and protective autophagy mediated by ROS. PTEN activation in response to DNA damage bridged DNA damage and prosurvival autophagy.

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