xmd-8-92 and Stomach-Neoplasms

Tobacco smoke is an important risk factor of gastric cancer. Epithelial-mesenchymal transition is a crucial pathophysiological process in cancer development. ERK5 regulation of epithelial-mesenchymal transition may be sensitive to cell types and/or the cellular microenvironment and its role in the epithelial-mesenchymal transition process remain elusive. Epigallocatechin-3-gallate (EGCG) is a promising chemopreventive agent for several types of cancers. In the present study we investigated the regulatory role of ERK5 in tobacco smoke-induced epithelial-mesenchymal transition in the stomach of mice and the preventive effect of EGCG. Exposure of mice to tobacco smoke for 12 weeks reduced expression of epithelial markers E-cadherin, ZO-1, and CK5, while the expression of mesenchymal markers Snail-1, Vimentin, and N-cadherin were increased. Importantly, we demonstrated that ERK5 modulated tobacco smoke-mediated epithelial-mesenchymal transition in mice stomach, as evidenced by the findings that tobacco smoke elevated ERK5 activation, and that tobacco smoke-triggered epithelial-mesenchymal transition was reversed by ERK5 inhibition. Treatment of EGCG (100 mg/kg BW) effectively attenuated tobacco smoke-triggered activation of ERK5 and epithelial-mesenchymal transition alterations in mice stomach. Collectively, these data suggested that ERK5 was required for tobacco smoke-triggered gastric epithelial-mesenchymal transition and that EGCG suppressed ERK5 activation to reverse tobacco smoke-triggered gastric epithelial-mesenchymal transition in BALB/c mice. These findings provide new insights into the mechanism of tobacco smoke-associated gastric tumorigenesis and the chemoprevention of tobacco smoke-associated gastric cancer.

Topics: Animals; Anticarcinogenic Agents; Benzodiazepinones; Biomarkers, Tumor; Carcinogenesis; Catechin; Dietary Supplements; Disease Models, Animal; Enzyme Activation; Epithelial-Mesenchymal Transition; Gastric Mucosa; Gene Expression Regulation, Neoplastic; Injections, Intraperitoneal; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 7; Phosphorylation; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Random Allocation; Smoking; Stomach Neoplasms

Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that belongs to the family of microtubule-associated proteins. Originally identified for its role in neurogenesis, DCLK1 has recently been shown to regulate biological processes outside of the CNS. DCLK1 is among the 15 most common putative driver genes for gastric cancers and is highly mutated across various other human cancers. However, our present understanding of how DCLK1 dysfunction leads to tumorigenesis is limited. Here, we provide evidence that DCLK1 kinase activity negatively regulates microtubule polymerization. We present the crystal structure of the DCLK1 kinase domain at 1.7 Å resolution, providing detailed insight into the ATP-binding site that will serve as a framework for future drug design. This structure also allowed for the mapping of cancer-causing mutations within the kinase domain, suggesting that a loss of kinase function may contribute to tumorigenesis.

Topics: Adenosine Triphosphate; Amino Acid Motifs; Animals; Antineoplastic Agents; Benzodiazepinones; Binding Sites; Crystallography, X-Ray; Doublecortin-Like Kinases; Gene Expression; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubules; Models, Molecular; Mutation; Protein Binding; Protein Domains; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Structure, Secondary; Pyrimidines; Recombinant Proteins; Stomach Neoplasms; Substrate Specificity; Tubulin Modulators; Xenograft Model Antitumor Assays