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

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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.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 30870948). We gratefully acknowledge Xinliang Ma (Department of Emergency Medicine, Thomas Jefferson University, USA), Feng Gao (Department of Physiology in our university), Hua Han (Department of Medical Genetics and Developmental Biology in our university) and Xiaoying Li (Institute of Endocrinology and Metabolism, Shanghai Jiaotong University School of Medicine, China) for their comments on the manuscript.

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Authors and Affiliations

  1. Department of Endocrinology, Xijing Hospital, The Fourth Military Medical University, 15 Changle West Road, 710032, Xi’an, Shaanxi, China

    Rongrong Hou, Jing Zhang, Hongwei Cao, Nanyan Zhang, Xiaomiao Li, Li Wang, Ying Xing, Deqiang Li & Qiuhe Ji

  2. Department of Endocrinology, Bethune International Peace Hospital, 398 Zhongshan West Road, 050082, Shijiazhuang, Hebei, China

    Rongrong Hou

  3. Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, 15 Changle West Road, 710032, Xi’an, Shaanxi, China

    Tao Yin

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  1. Rongrong Hou
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Correspondence to Qiuhe Ji.

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Rongrong Hou, Jing Zhang authors contributed equally to this work.

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Hou, R., Zhang, J., Yin, T. et al. Upregulation of PTEN by peroxynitrite contributes to cytokine-induced apoptosis in pancreatic β-cells. Apoptosis 15, 877–886 (2010). https://doi.org/10.1007/s10495-010-0510-z

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