Abstract
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.
Highlights
Lung cancer is the leading cause of cancer-related death worldwide
We observed increased annexin V-positive cells, along with elevated expression of cleaved poly(ADP-ribose) polymerase (PARP) and caspase-3 proteins, in DARPP-32 knockdown cell lines compared to controls (Fig. 1d–i), suggesting that DARPP-32 inhibits apoptosis in lung cancer cells
For the first time to our knowledge, we demonstrate that DARPP32 and its splice variant t-DARPP stimulate lung cancer cell survival and migration to promote oncogenesis, and we show that elevated t-DARPP isoform levels in non-small-cell lung cancer (NSCLC) patients are associated with increased tumor staging and worsened patient survival
Summary
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. The N-terminally truncated isoform of DARPP32, termed t-DARPP, was found to utilize a unique alternative first exon located within intron 1 of DARPP-32 and to lack the first 36 amino acids of DARPP-32, including the T34 phosphorylation residue required for DARPP-32-mediated PP-1 inhibition[9] Overexpression of both DARPP-32 and t-DARPP has been observed in 68% of gastric cancers[9,10]. T-DARPP overexpression was shown to promote activation of insulin-like growth factor-1 receptor signaling to regulate glucose metabolism as a mechanism of trastuzumab resistance in breast cancer cells[20]. A recent report has suggested that proinflammatory Helicobacter pylori infection and canonical NF-κB1 activation play an important role in the regulation of DARPP-32 expression, which has been shown to counteract infection-induced cell death and promote cell survival in gastric carcinogenesis[35]
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