title: Upregulation of PTEN by peroxynitrite contributes to cytokine-induced apoptosis in pancreatic beta-cells.
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 beta-cells leads to resistance to streptozotocin (STZ)-induced diabetes, but the mechanism is unclear. One major mechanism underlying STZ toxicity is cytokine-mediated beta-cell destruction in which oxidative stress plays a key role. The present study investigated the role of PTEN in cytokine-induced beta-cell apoptosis, and further explored whether oxidative stress, particularly peroxynitrite formation, could regulate PTEN-Akt pathway. Incubation of betaTC-6 cells with cytokine mixture (IL-1beta, TNF-alpha, and IFN-gamma) or exogenous peroxynitrite significantly increased apoptotic cell percentage, elevated PTEN and p-PTEN levels, and inhibited Akt activation. Transfection with PTEN-specific siRNA protected betaTC-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 beta-cell apoptosis. These findings suggest that peroxynitrite-mediated PTEN upregulation plays an important role in cytokine-induced pancreatic beta-cell apoptosis.
authors.affiliation: Department of Endocrinology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Hou
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Yin
authors.forename: Hongwei
authors.initials: H
authors.lastname: Cao
authors.forename: Nanyan
authors.initials: N
authors.lastname: Zhang
authors.forename: Xiaomiao
authors.initials: X
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Xing
authors.forename: Deqiang
authors.initials: D
authors.lastname: Li
authors.forename: Qiuhe
authors.initials: Q
authors.lastname: Ji
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D030421:Peroxynitrous Acid; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse