gkt137831 and Esophageal-Neoplasms

Nox4 has been associated with tumor progression in various types of malignancies. This study aimed to evaluate the importance of the expression of Nox4 in patients undergoing curative esophagectomy for esophageal squamous cell carcinoma.. We reviewed retrospectively 121 patients with esophageal squamous cell carcinoma who had undergone a curative esophagectomy, including 67 patients with overexpression and 54 patients with low expression of Nox4 as evaluated by immunohistochemical analysis. In addition, 2 esophageal squamous cell carcinoma cell lines, TE11 and KYSE270, were treated with the Nox4 inhibitor GKT-137831 to explore the expression of Nox4, cell proliferative activity, and selected downstream pathways in these esophageal squamous cell carcinoma cell lines by Western blot analysis.. Univariate analysis showed that T1-2 status, absence of nodal metastasis, and low Nox4 expression were associated with greater disease-free survival (P = .001) and overall survival (P < .001), and Nox4 overexpression was an independent prognostic factor of worse disease-free survival and overall survival (P = .013 and P = .007, respectively). The esophageal squamous cell carcinoma cell lines treated with the Nox4 inhibitor GKT-137831 showed decreased cell proliferation in a dose-dependent manner (P < .01). Western blot analysis demonstrated that expression of AKT, phosphorylated AKT, mammalian target of rapamycin, and phosphorylated mammalian target of rapamycin were less in esophageal squamous cell carcinoma cells treated with the Nox4 inhibitor (P < .01).. This study suggests that Nox4 overexpression is a poor prognostic factor for patients with esophageal squamous cell carcinoma undergoing curative esophagectomy.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Disease-Free Survival; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Esophagus; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; NADPH Oxidase 4; Neoplasm Staging; Prognosis; Pyrazoles; Pyrazolones; Pyridines; Pyridones; Retrospective Studies

Cancer-associated fibroblasts (CAFs) are tumor-promoting and correlate with poor survival in many cancers, which has led to their emergence as potential therapeutic targets. However, effective methods to manipulate these cells clinically have yet to be developed.. CAF accumulation and prognostic significance in head and neck cancer (oral, n = 260; oropharyngeal, n = 271), and colorectal cancer (n = 56) was analyzed using immunohistochemistry. Mechanisms regulating fibroblast-to-myofibroblast transdifferentiation were investigated in vitro using RNA interference/pharmacological inhibitors followed by polymerase chain reaction (PCR), immunoblotting, immunofluorescence, and functional assays. RNA sequencing/bioinformatics and immunohistochemistry were used to analyze NAD(P)H Oxidase-4 (NOX4) expression in different human tumors. NOX4's role in CAF-mediated tumor progression was assessed in vitro, using CAFs from multiple tissues in Transwell and organotypic culture assays, and in vivo, using xenograft (n = 9-15 per group) and isograft (n = 6 per group) tumor models. All statistical tests were two-sided.. Patients with moderate/high levels of myofibroblastic-CAF had a statistically significant decrease in cancer-specific survival rates in each cancer type analyzed (hazard ratios [HRs] = 1.69-7.25, 95% confidence intervals [CIs] = 1.11 to 31.30, log-rank P ≤ .01). Fibroblast-to-myofibroblast transdifferentiation was dependent on a delayed phase of intracellular reactive oxygen species, generated by NOX4, across different anatomical sites and differentiation stimuli. A statistically significant upregulation of NOX4 expression was found in multiple human cancers (P < .001), strongly correlating with myofibroblastic-CAFs (r = 0.65-0.91, adjusted P < .001). Genetic/pharmacological inhibition of NOX4 was found to revert the myofibroblastic-CAF phenotype ex vivo (54.3% decrease in α-smooth muscle actin [α-SMA], 95% CI = 10.6% to 80.9%, P = .009), prevent myofibroblastic-CAF accumulation in vivo (53.2%-79.0% decrease in α-SMA across different models, P ≤ .02) and slow tumor growth (30.6%-64.0% decrease across different models, P ≤ .04).. These data suggest that pharmacological inhibition of NOX4 may have broad applicability for stromal targeting across cancer types.

Topics: Actins; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Animals; Cancer-Associated Fibroblasts; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Count; Cell Transdifferentiation; Colorectal Neoplasms; Disease Progression; Esophageal Neoplasms; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Mice; Middle Aged; Mouth Neoplasms; Myofibroblasts; NADPH Oxidase 4; NADPH Oxidases; Neoplasm Transplantation; Oropharyngeal Neoplasms; Phenotype; Pyrazoles; Pyrazolones; Pyridines; Pyridones; Reactive Oxygen Species; RNA Interference; Survival Rate; Up-Regulation