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 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 that 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.
Bibliographical noteFunding Information:
This work was supported by The Hormel Foundation, Austin “Paint the Town Pink”, National Institutes of Health, National Cancer Institute R00-CA187035 funding to L.H. H. and K12-CA090628 to A.S.M. The Hormel Institute SURE program supported E.N.D. and A.M.C. We thank Dr. Debabrata Mukhopadhyay at Mayo Clinic in Jacksonville, FL, for his valuable support and contributions to the development of this project, including sharing reagents and advice. We appreciate the contributions of Todd Schuster, the shared facilities manager at The Hormel Institute, to flow cytometry-based apoptosis and BrdU assays. We thank Kim Klukas and The Hormel Institute animal facilities staff for providing excellent animal care and husbandry. We are grateful to Shirley Bradley and Sandip Suresh for their research contributions to this project as a rotating graduate student and a summer undergraduate intern, respectively, at Mayo Clinic. We thank Dr. Wael El-Rifai at Vanderbilt University in Nashville, TN, for sharing DARPP-32 reagents and Dr. Yasuhiro Ikeda at Mayo Clinic in Rochester, MN, for providing constructs to stably luciferase label lung cancer cells. We thank the Mayo Clinic Pathology Research Core for assistance with immunohistochemistry staining and The Hormel Institute for administrative and institutional support.
© 2018, The Author(s).