Stauprimide is a staurosporine analog that promotes embryonic stem cell (ESC) differentiation by inhibiting nuclear localization of the MYC transcription factor NME2, which in turn results in downregulation of MYC transcription. Given the critical role the oncogene MYC plays in tumor initiation and maintenance, we explored the potential of stauprimide as an anticancer agent. Here we report that stauprimide suppresses MYC transcription in cancer cell lines derived from distinct tissues. Using renal cancer cells, we confirmed that stauprimide inhibits NME2 nuclear localization. Gene expression analysis also confirmed the selective down-regulation of MYC target genes by stauprimide. Consistent with this activity, administration of stauprimide inhibited tumor growth in rodent xenograft models. Our study provides a unique strategy for selectively targeting MYC transcription by pharmacological means as a potential treatment for MYCdependent tumors.MYC | stauprimide | NME2 | nuclear localization | cancer T he transcription factor MYC participates in diverse cellular processes by regulating the transcription of a large number of genes involved in gene expression, cell division, apoptosis, cell adhesion, stem cell self-renewal and differentiation, and metabolism (1-3). MYC is an oncogene whose expression is elevated in up to 75% of all cancers with various tissue origins (4); MYC expression levels also correlate with prognostic outcomes in patients of various types of malignancies (5, 6). In addition to its well-established roles in tumor initiation and cancer cell survival and proliferation, MYC has been shown to be involved in tumor microenvironment remodeling, drug resistance, and cancer stem cell maintenance (7-9). Recent studies have also revealed a role for MYC in regulating the transcription of immune checkpoint genes, including CD47 and PD-L1 in cancer cells, suggesting that MYC is involved in cancer escape from immune surveillance (10).Overexpression of MYC is able to induce malignant transformation in skin (11), lung (12), liver (13), breast (14, 15), and hematopoietic cells (16) in transgenic mouse models, and termination of MYC overexpression results in halted cancer cell proliferation, increased apoptosis and terminal differentiation, and tumor regression. Furthermore, inhibition of endogenous MYC by the inducible expression of a dominant-negative variant of MYC, Omomyc, is able to induce tumor regression in transgenic mouse models of lung cancer (17). More intriguingly, transient deactivation of MYC overexpression (18) and episodic expression of Omomyc (19) have been shown to induce irreversible tumor regression in osteosarcoma and lung cancer transgenic mouse models, suggesting the potential of MYCtargeted anticancer therapies.Drug discovery efforts have attempted to directly and indirectly modulate MYC-dependent transcription. For example, compounds have been identified that disrupt the interaction between MYC and its transcriptional partner MAX to suppress downstream gene transcription (20)(21)(22)(23)(2...
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and lung inflammation resulting in a progressive decline in lung function whose principle cause is cigarette smoke. MAP3K19 is a novel kinase expressed predominantly by alveolar and interstitial macrophages and bronchial epithelial cells in the lung. We found that MAP3K19 mRNA was overexpressed in a limited sampling of lung tissue from COPD patients, and a closer examination found it to be overexpressed in bronchoalveolar macrophages from COPD patients, as well as the bronchial epithelium and inflammatory cells in the lamina propria. We further found MAP3K19 to be induced in various cell lines upon environmental stress, such as cigarette smoke, oxidative and osmotic stress. Exogenous expression of MAP3K19 in cells caused an upregulation of transcriptionally active NF-κB, and secretion of the chemokines CXCL-8, CCL-20 and CCL-7. Inhibition of MAP3K19 activity by siRNA or small molecular weight inhibitors caused a decrease in cigarette smoke-induced inflammation in various murine models, which included a decrease in pulmonary neutrophilia and KC levels. In a chronic cigarette smoke model, inhibition of MAP3K19 significantly attenuated emphysematous changes in airway parenchyma. Finally, in a viral exacerbation model, mice exposed to cigarette smoke and influenza A virus showed a decrease in pulmonary neutrophilia, pro-inflammatory cytokines and viral load upon inhibition of MAP3K19. Collectively, these results suggest that inhibition of MAP3K19 may represent a novel strategy to target COPD that promises to have a potential therapeutic benefit for patients.
lipid peroxidation, oxidative stress and aberrant metabolism resulting from the LPS induced inflammatory process. Conclusion: These results confirm the ability of our DNA adductomic approach to characterize the DNA damage deriving from these exposures. Our comprehensive DNA adductomic approach contributes to the development of new tools needed to investigate lung carcinogenesis, to elucidate its mechanisms and dissect the molecular pathways involved in inflammation-driven lung cancer, with the ultimate goal of identifying preventive and therapeutic strategies.
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