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

Alam, S. K.; Astone, M.; Liu, P.; Hall, S. R.; Coyle, A. M.; Dankert, E. N.; Hoffman, D. K.; Zhang, W.; Kuang, R.; Roden, A. C.; Mansfield, A. S.; Hoeppner, L. H.

doi:10.1101/229658

bioRxiv · 10.1101/229658

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

Alam, S. K.·Astone, M.·Liu, P.·Hall, S. R.·Coyle, A. M.·Dankert, E. N.·Hoffman, D. K.·Zhang, W.·Kuang, R.·Roden, A. C.·Mansfield, A. S.·Hoeppner, L. H.

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Abstract

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- (IKK) that promotes NSCLC cell migration through non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells 2 (NF-{kappa}B2) 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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Alam, S. K., Astone, M., Liu, P., Hall, S. R., Coyle, A. M., Dankert, E. N., Hoffman, D. K., Zhang, W., Kuang, R., Roden, A. C., Mansfield, A. S., Hoeppner, L. H.. 2017-12-06. DARPP-32 and t-DARPP promote lung cancer growth through IKKα-dependent cell migration and Akt/Erk-mediated cell survival. https://doi.org/10.1101/229658

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