No abstract

Acyclic retinoid (ACR), a novel synthetic retinoid, has been demonstrated by us to inhibit the in vitro growth of human hepatoma cells, and this effect was associated with modification of cell cycle control molecules, suggesting that this agent may be useful in the chemoprevention and therapy of various types of malignancies. However, whether or not ACR exerts anticancer activities on human colon carcinoma cells has not yet been elucidated. The purpose of this study was to examine the inhibitory effects of ACR in human colon carcinoma cells and to characterize the molecular mechanism of action of this agent. ACR inhibited the growth of the HCT116 and SW480 human colon carcinoma cell lines with IC 50 values of about 30 and 60 μM, respectively. ACR also induced G1-phase cell cycle arrest and apoptosis in these cell lines. When the HCT116 cells were treated with 5-25 μM ACR, there was a marked decrease in the cellular levels of cyclin D1 mRNA and an approximate 2.5-to 3-fold increase in those of p21 CIP1 mRNA, and this induction occurred via a p53-independent mechanism. Furthermore, ACR induced a dose-dependent mRNA elevation of differentiation markers at concentrations of ACR that affect the levels of expression of p21 CIP1 . These novel results suggest that ACR inhibits cell proliferation by inducing G1 arrest and apoptosis and that cyclin D1 and p21 CIP1 play critical roles in the molecular mechanisms of growth inhibition and differentiation induced by ACR. Collectively, these findings provide further evidence that ACR may be a potential agent for the chemoprevention and therapy of human colon cancer.

Abstract. This study aimed to investigate whether glucose transporter-1 (GLUT-1) expression in a pretreatment esophageal cancer biopsy was predictive of clinical outcomes in patients with esophageal cancer undergoing concurrent chemoradiotherapy (CRT). A total of 25 patients with esophageal cancer treated with concurrent CRT were reviewed. Radiotherapy was administered up to total doses of 40-66.6 Gy (median 66.6 Gy) with a single fraction of 1.8-2 Gy. Regarding chemotherapy, cisplatin (80 mg/m 2 on day 1) and 5-fluorouracil (800 mg/m 2 on days 2-6) were used concurrently with radiotherapy, every 3-4 weeks for a total of 1-2 courses. Tissue samples from esophageal carcinoma were obtained from the 25 patients by biopsy prior to concurrent CRT, and a semiquantitative analysis of GLUT-1 expression was performed using immunohistochemical staining. High GLUT-1 expression was observed in 7 of 25 (28%) patients, and GLUT-1 expression was significantly correlated with clinical T stage (p=0.0454), clinical N stage (p=0.0324) and initial response to CRT (p=0.0185). Patients with a high GLUT-1 expression had significantly poorer local control (LC) (5-year LC 28.6%) than those with a low expression (5-year LC 73.4%, p<005). Multivariate analysis revealed that GLUT-1 and the number of chemotherapy courses were independent prognostic factors for LC. Patients with a high GLUT-1 expression had significantly lower recurrence-free survival (RFS) compared to those with a low GLUT-1 expression (p=0.0405). Multivariate analysis revealed that GLUT-1, the number of chemotherapy courses and clinical M stage were independent prognostic factors for RFS. GLUT-1 expression was significantly correlated with clinical T stage, clinical N stage and initial response to concurrent CRT, and was predictive of LC and RFS for patients with esophageal cancer treated with concurrent CRT.

Inflammation is associated with disease progression and, by largely unknown mechanisms, has been said to drive oncogenesis. At inflamed sites, neutrophils deploy a potent antimicrobial arsenal that includes proteinases, antimicrobial peptides, and ROS. Reactive oxygen species (ROSs) induce chemokines. In the present study, the concentrations of IL-8 in culture supernatants of HeLa cells treated with ROS were determined by enzyme-linked immunosorbent assay. We used o-phenanthroline to deplete Fe2+ in order to investigate the mechanisms through which ROSs induce IL-8 secretion in our system. The iron chelator o-phenanthroline effectively inhibited H2O2-induced ERK2 activation. Enzyme-linked immunosorbent assays showed that IL-8 protein secretion was elevated in ROS-treated HeLa cells. When Fe2+ was removed from these cells, IL-8 secretion was inhibited. Collectively, these results indicate that Fe2+-mediated Erk pathway activation is an important signal transduction pathway in ROS-induced IL-8 secretion in epithelial cells.

To date, the major role of HPV16E6 in cancer has been considered to be its ability to inhibit the p53 tumor-suppressor protein, thereby thwarting p53-mediated cytotoxic responses to cellular stress signals. Here, we show that HPV16E6-dependent c-fos oncogenic protein expression contributes to AP-1 complex formation under oxidative stress in SiHa cells (HPV16-positive squamous cell carcinoma of the cervix). In addition, we examined the role of HPV16E6 in TGF-α-induced c-fos expression and found that the c-fos protein expression induced by TGF-α is HPV16E6 dependent. Thus, our results provide the first evidence that HPV16E6 contributes to AP-1 complex formation after both ligand-dependent and independent EGFR activation, suggesting a new therapeutic approach to the treatment of HPV-associated tumors.