Akt Kinase Mediates the Prosurvival Effect of Smoking Compounds in Pancreatic Ductal Cells

作者：Park Chang Hwan; Lee In Seok; Grippo Paul; Pandol Stephen J; Gukovskaya Anna S; Edderkaoui Mouad^*

来源：Pancreas, 2013, 42(4): 655-662.

DOI：10.1097/MPA.0b013e3182762928

• pancreatic cancer
• smoking
• apoptosis
• autophagy

Objectives: Cigarette smoking is a major risk factor for pancreatic cancer (PaCa). However, the mechanisms of smoking-induced PaCa remain unknown. Here we investigated the effect of smoking compounds on cell death pathways in pancreatic ductal cells, precursors of PaCa. %26lt;br%26gt;Methods: Human pancreatic ductal cells (HPDE6-c7) were cultured with cigarette smoke extract (CSE) or smoking compound 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Apoptosis and autophagy were assessed by DNA fragmentation and immunofluorescence, respectively. %26lt;br%26gt;Results: Exposure to CSE or NNK decreased DNA fragmentation and up-regulated Bcl(XL). Akt kinase was activated by smoking compounds through reactive oxygen species-dependent mechanism. Specifically, Akt activation was prevented by inhibition of nicotinamide adenine dinucleotide oxidase. Molecular or pharmacologic inhibitions of Akt prevented the antiapoptotic effect of smoking compounds. Smoking compounds stimulated rapid (1 hour) and transient activation of 5%26apos;-adenosine monophosphate-activated protein kinase and formation of autophagic vacuoles, indicating stimulation of autophagy. Repeated exposure to CSE/NNK (48 hours or longer) abolished the early activation of autophagic markers. Inhibition of Akt prevented the antiautophagic effect of long exposure to smoking compounds, indicating that smoking-induced late activation of Akt prevents autophagy. %26lt;br%26gt;Conclusions: Long exposure of pancreatic ductal cells to smoking compounds inhibited apoptosis and autophagy. The results revealed a central role for Akt kinase in mediating key procarcinogenic effects of smoking compounds.

• 出版日期2013-5
• 单位西北大学