Apoptosis

, Volume 15, Issue 8, pp 877–886

Upregulation of PTEN by peroxynitrite contributes to cytokine-induced apoptosis in pancreatic β-cells

  • Rongrong Hou
  • Jing Zhang
  • Tao Yin
  • Hongwei Cao
  • Nanyan Zhang
  • Xiaomiao Li
  • Li Wang
  • Ying Xing
  • Deqiang Li
  • Qiuhe Ji
Original Paper

DOI: 10.1007/s10495-010-0510-z

Cite this article as:
Hou, R., Zhang, J., Yin, T. et al. Apoptosis (2010) 15: 877. doi:10.1007/s10495-010-0510-z

Abstract

Phosphatase and tensin homolog (PTEN), a tumor suppressor gene, by negatively regulating the PI3K-Akt signaling pathway, participates in multiple biological processes such as cell proliferation, apoptosis, differentiation, and migration. Recent studies show that selective deletion of PTEN in pancreatic β-cells leads to resistance to streptozotocin (STZ)-induced diabetes, but the mechanism is unclear. One major mechanism underlying STZ toxicity is cytokine-mediated β-cell destruction in which oxidative stress plays a key role. The present study investigated the role of PTEN in cytokine-induced β-cell apoptosis, and further explored whether oxidative stress, particularly peroxynitrite formation, could regulate PTEN-Akt pathway. Incubation of βTC-6 cells with cytokine mixture (IL-1β, TNF-α, and IFN-γ) or exogenous peroxynitrite significantly increased apoptotic cell percentage, elevated PTEN and p-PTEN levels, and inhibited Akt activation. Transfection with PTEN-specific siRNA protected βTC-6 cells from cytokine or peroxynitrite-mediated cell apoptosis and partially reversed Akt inhibition. Furthermore, nitrotyrosine formation, an indicator of peroxynitrite production, was significantly elevated after cytokine treatment. Preventing peroxynitrite formation by administrating NAC/l-NMMA, or scavenging peroxynitrite directly by UA, attenuated cytokine-induced PTEN upregulation, Akt inhibition, and β-cell apoptosis. These findings suggest that peroxynitrite-mediated PTEN upregulation plays an important role in cytokine-induced pancreatic β-cell apoptosis.

Keywords

Apoptosis PTEN Cytokine Peroxynitrite Pancreatic β-cell 

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Rongrong Hou
    • 1
    • 2
  • Jing Zhang
    • 1
  • Tao Yin
    • 3
  • Hongwei Cao
    • 1
  • Nanyan Zhang
    • 1
  • Xiaomiao Li
    • 1
  • Li Wang
    • 1
  • Ying Xing
    • 1
  • Deqiang Li
    • 1
  • Qiuhe Ji
    • 1
  1. 1.Department of Endocrinology, Xijing HospitalThe Fourth Military Medical UniversityXi’anChina
  2. 2.Department of EndocrinologyBethune International Peace HospitalShijiazhuangChina
  3. 3.Department of Cardiology, Xijing HospitalThe Fourth Military Medical UniversityXi’anChina

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