Tobacco Carcinogen-Induced Production of GM-CSF Activates CREB to Promote Pancreatic Cancer

Although smoking is a significant risk factor for pancreatic cancer (PDAC), the molecular mechanisms underlying PDAC development and progression in smokers are still unclear. Here we show the role of cAMP response element-binding protein (CREB) in the pathogenesis of smoking-induced PDAC. Smokers had significantly higher levels of activated CREB when compared to non-smokers. Cell lines derived from normal pancreas and pancreatic intraepithelial neoplasm (PanIN) exhibited low baseline pCREB levels compared to PDAC cell lines. Furthermore, elevated CREB expression correlated with reduced survival in PDAC patients. Depletion of CREB significantly reduced tumor burden after tobacco-specific nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) treatment, suggesting a CREB-dependent contribution to PDAC growth and progression in smokers. Conversely, NNK accelerated PanIN lesion and PDAC formation via GM-CSF mediated activation of CREB in a PDAC mouse model. CREB inhibition (CREBi) in mice more effectively reduced primary tumor burden compared to control or GM-CSF blockade alone following NNK exposure. GM-CSF played a role in the recruitment of tumor associated macrophages (TAM) and Treg expansion and promotion, whereas CREBi significantly reduced TAM and Treg populations in NNK-exposed mice. Overall, these results suggest that NNK exposure leads to activation of CREB through GM-CSF, promoting inflammatory and Akt pathways. Direct inhibition of CREB, but not GM-CSF, effectively abrogates these effects and inhibits tumor progression, offering a viable therapeutic strategy for PDAC patients.

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