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DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKα-dependent cell migration

2018; Nature Portfolio; Volume: 1; Issue: 1 Linguagem: Inglês

10.1038/s42003-018-0050-6

2399-3642

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,

Peptidase Inhibition and Analysis

Lung cancer is the leading cause of cancer-related death worldwide. Here we demonstrate that elevated expression of dopamine and cyclic adenosine monophosphate-regulated phosphoprotein, Mr 32000 (DARPP-32) and its truncated splice variant t-DARPP promote 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 shows that t-DARPP expression is elevated with increasing tumor (T) stage. Our data suggest that DARPP-32 isoforms serve as a negative prognostic marker associated with increasing stages of NSCLC and may represent a novel therapeutic target.