Complete Inhibition of Phosphatase and Tensin Homolog Promotes the Normal and Oxygen-glucose Deprivation/reperfusion-injured PC12 Cells to Cell Death

Overview

Journal J Cardiovasc Thorac Res

Specialty Cardiology & Vascular Diseases

Date 2018 Aug 18

PMID 30116506

Citations 2

Authors

Sohrab Minaei Beyrami

Mohammad Hasan Khadem Ansari

Yousef Rasemi

Nader Shakib

Pouran Karimi

Affiliations

Soon will be listed here.

Abstract

Lipid phosphatase and tensin homolog deleted from chromosome 10 (PTEN) antagonizes phosphoinositide 3-kinase (PI3K)/AKT cell survival pathway. The effect of PTEN inhibitors has been rarely examined on cell survival following reperfusion injury. In this study, we investigated the neuroprotective effect of SF1670, as a new PTEN inhibitor, on an in vitro stroke-like model. PC12 cells were exposed to oxygen-glucose deprivation/reperfusion (OGD/R). The cells were treated in five conditions as follows: normoxic normoglycemic (NO/NG); 60 minutes OGD; 60 minutes OGD and 6 h reperfusion (OGD/R); OGD/R treated with 10 µM SF1670 (OGD/R-SF), and NO/NG treated with 10 µM SF1670 (NO/NG-SF). Then, phosphorylation levels of AKT, P38 in PC12 cells were measured by immunoblotting. The cell viability was also determined by colorimetric assay. The results of immunoblotting revealed that following OGD/R the levels of phospho-AKT (p-AKT) significantly decreased, compared to NO/NG cells ( < 0.05). However, the ratio of p-AKT/total AKT significantly increased in the presence of SF1670 in the OGD/R-SF group, compared to the OGD/R condition. On the other hand, SF1670 significantly reduced the p-P38 MAPK and p-JNK levels, compared to OGD/R cells. Moreover, cell viability significantly decreased in the OGD and OGD/R condition compared to NO/NG cells. Surprisingly, SF-treated cells (OGD/R-SF and NO/NG-SF group) showed low cell viability compared to NO/NG condition. Overall, our results demonstrated that complete inhibition of phosphatase activity of PTEN not only did not exhibit neuroprotective effect but also promoted PC12-deprived cells to death.

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References

Xu X, Chua C, Gao J, Chua K, Wang H, Hamdy R . Neuroprotective effect of humanin on cerebral ischemia/reperfusion injury is mediated by a PI3K/Akt pathway. Brain Res. 2008; 1227:12-8. PMC: 2575816. DOI: 10.1016/j.brainres.2008.06.018. View

Jiang M, Li J, Peng Q, Liu Y, Liu W, Luo C . Neuroprotective effects of bilobalide on cerebral ischemia and reperfusion injury are associated with inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation. J Neuroinflammation. 2014; 11:167. PMC: 4189683. DOI: 10.1186/s12974-014-0167-6. View

Guan J, Du S, Lv T, Qu S, Fu Q, Yuan Y . Oxygen-glucose deprivation preconditioning protects neurons against oxygen-glucose deprivation/reperfusion induced injury via bone morphogenetic protein-7 mediated ERK, p38 and Smad signalling pathways. Clin Exp Pharmacol Physiol. 2015; 43(1):125-34. DOI: 10.1111/1440-1681.12492. View

Liao J, Marumoto T, Yamaguchi S, Okano S, Takeda N, Sakamoto C . Inhibition of PTEN tumor suppressor promotes the generation of induced pluripotent stem cells. Mol Ther. 2013; 21(6):1242-50. PMC: 3677303. DOI: 10.1038/mt.2013.60. View

Adams Jr H, Bendixen B, Kappelle L, Biller J, Love B, Gordon D . Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993; 24(1):35-41. DOI: 10.1161/01.str.24.1.35. View

Zhang L, Qu Y, Tang J, Chen D, Fu X, Mao M . PI3K/Akt signaling pathway is required for neuroprotection of thalidomide on hypoxic-ischemic cortical neurons in vitro. Brain Res. 2010; 1357:157-65. DOI: 10.1016/j.brainres.2010.08.007. View

Adams Jr H, Brott T, Furlan A, Gomez C, Grotta J, Helgason C . Guidelines for Thrombolytic Therapy for Acute Stroke: a Supplement to the Guidelines for the Management of Patients with Acute Ischemic Stroke. A statement for healthcare professionals from a Special Writing Group of the Stroke Council, American.... Stroke. 1996; 27(9):1711-8. View

Achiwa Y, Hasegawa K, Udagawa Y . Regulation of the phosphatidylinositol 3-kinase-Akt and the mitogen-activated protein kinase pathways by ursolic acid in human endometrial cancer cells. Biosci Biotechnol Biochem. 2007; 71(1):31-7. DOI: 10.1271/bbb.60288. View

Chen X, Kintner D, Baba A, Matsuda T, Shull G, Sun D . Protein aggregation in neurons following OGD: a role for Na+ and Ca2+ ionic dysregulation. J Neurochem. 2009; 112(1):173-82. PMC: 2817933. DOI: 10.1111/j.1471-4159.2009.06438.x. View

10.

. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333(24):1581-7. DOI: 10.1056/NEJM199512143332401. View

11.

Ma Y, Zhao P, Zhu J, Yan C, Li L, Zhang H . Naoxintong Protects Primary Neurons from Oxygen-Glucose Deprivation/Reoxygenation Induced Injury through PI3K-Akt Signaling Pathway. Evid Based Complement Alternat Med. 2016; 2016:5815946. PMC: 4754490. DOI: 10.1155/2016/5815946. View

12.

Coulthard L, White D, Jones D, McDermott M, Burchill S . p38(MAPK): stress responses from molecular mechanisms to therapeutics. Trends Mol Med. 2009; 15(8):369-79. PMC: 3016890. DOI: 10.1016/j.molmed.2009.06.005. View

13.

Duman B, Sahin B, Acikalin A, Ergin M, Zorludemir S . PTEN, Akt, MAPK, p53 and p95 expression to predict trastuzumab resistance in HER2 positive breast cancer. J BUON. 2013; 18(1):44-50. View

14.

Li W, Huang R, Chen Z, Yan L, Simpkins J, Yang S . PTEN degradation after ischemic stroke: a double-edged sword. Neuroscience. 2014; 274:153-61. PMC: 4167413. DOI: 10.1016/j.neuroscience.2014.05.027. View

15.

Ozbek E, Cekmen M, Ilbey Y, Simsek A, Polat E, Somay A . Atorvastatin prevents gentamicin-induced renal damage in rats through the inhibition of p38-MAPK and NF-kappaB pathways. Ren Fail. 2009; 31(5):382-92. DOI: 10.1080/08860220902835863. View

16.

Chan P . Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab. 2001; 21(1):2-14. DOI: 10.1097/00004647-200101000-00002. View

17.

Ning K, Pei L, Liao M, Liu B, Zhang Y, Jiang W . Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN. J Neurosci. 2004; 24(16):4052-60. PMC: 6729419. DOI: 10.1523/JNEUROSCI.5449-03.2004. View

18.

Shin W, Park S, Kim E . Protective effect of anthocyanins in middle cerebral artery occlusion and reperfusion model of cerebral ischemia in rats. Life Sci. 2006; 79(2):130-7. DOI: 10.1016/j.lfs.2005.12.033. View

19.

Zhou J, Jia L, Hu Z, Wang Y . Pharmacological Inhibition of PTEN Aggravates Acute Kidney Injury. Sci Rep. 2017; 7(1):9503. PMC: 5572703. DOI: 10.1038/s41598-017-10336-8. View

20.

Walker C, Liu N, Xu X . PTEN/PI3K and MAPK signaling in protection and pathology following CNS injuries. Front Biol (Beijing). 2013; 8(4). PMC: 3858858. DOI: 10.1007/s11515-013-1255-1. View