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DARPP-32 and t-DARPP promote lung cancer growth through IKKα-dependent cell migration and Akt/Erk-mediated cell survival

By Sk. Kayum Alam, Matteo Astone, Ping Liu, Stephanie R Hall, Abbygail M Coyle, Erin N Dankert, Dane K Hoffman, Wei Zhang, Rui Kuang, Anja C Roden, Aaron S Mansfield, Luke H. Hoeppner

Posted 06 Dec 2017
bioRxiv DOI: 10.1101/229658 (published DOI: 10.1038/s42003-018-0050-6)

Lung cancer is the leading cause of cancer-related death worldwide. In this study, we demonstrate that elevated expression of dopamine and cyclic adenosine monophosphate-regulated phosphoprotein, Mr 32000 (DARPP-32) and its truncated splice variant t-DARPP promotes lung tumor growth, while abrogation of DARPP-32 expression in human non-small cell lung cancer (NSCLC) cells reduces tumor growth in orthotopic mouse models. We observe a novel physical interaction between DARPP-32 and inhibitory kappa B kinase-α (IKKα) that promotes NSCLC cell migration through non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells 2 (NF-κB2) signaling. Bioinformatics analysis of 513 lung adenocarcinoma patients reveals elevated t-DARPP isoform expression is associated with poor overall survival. Histopathological investigation of 62 human lung adenocarcinoma tissues also showed that t-DARPP expression is elevated with increasing tumor (T) stage. Our data suggest that DARPP-32 is a negative prognostic marker associated with increasing stages of NSCLC and may represent a novel therapeutic target.

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