Journal
APOPTOSIS
Volume 15, Issue 8, Pages 877-886Publisher
SPRINGER
DOI: 10.1007/s10495-010-0510-z
Keywords
Apoptosis; PTEN; Cytokine; Peroxynitrite; Pancreatic beta-cell
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Funding
- National Natural Science Foundation of China [30870948]
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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 beta TC-6 cells with cytokine mixture (IL-1 beta, 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 beta TC-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.
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