Eppley Institute for Research in Cancer and Allied Diseases

About: Eppley Institute for Research in Cancer and Allied Diseases is a based out in . It is known for research contribution in the topics: Pancreatic cancer & Cancer. The organization has 965 authors who have published 1396 publications receiving 58994 citations.

MUC4 stabilizes HER2 expression and maintains the cancer stem cell population in ovarian cancer cells

Abstract: Recent evidence has suggested that the capability of cancer to grow, propagate and relapse after therapy is dependent on a small subset of the cell population within the tumor, called cancer stem cells. Therefore, this subpopulation of cells needs to be targeted with different approaches by identification of unique stem-cell specific target antigens. One of the well known tumor antigens is the epithelial cell mucin MUC4, which is aberrantly expressed in ovarian cancer as compared to the normal ovary and plays a pivotal role in the aggressiveness and metastasis of ovarian cancer cells. In the present study, we aimed to analyze the cancer stem cell population in MUC4 overexpressed ovarian cancer cells. MUC4 was ectopically overexpressed in SKOV3 ovarian cancer cells. Western blot analysis was performed for MUC4, HER2, CD133, ALDH1 and Shh expression in MUC4 overexpressed cells. Confocal analysis of MUC4, HER2 and CD133 was also done in the MUC4 overexpressed cells. CD133 and Hoechst33342 dye staining was used to analyze the cancer stem cell population via FACS method in SKOV3-MUC4 cells. MUC4 overexpressed SKOV3 cells showed an increased expression of HER2 compared to control cells. MUC4 overexpression leads to increased (0.1%) side population (SP) and CD133-positive cancer stem cells compared to the control cells. Interestingly, the tumor sphere type circular colony formation was observed only in the MUC4 overexpressed ovarian cancer cells. Furthermore, the cancer stem cell marker CD133 was expressed along with MUC4 in the isolated circular colonies as analyzed by both confocal and western blot analysis. HER2 and cancer stem cell specific marker ALDH1 along with Shh, a self-renewal marker, showed increased expression in the isolated circular colonies compared to MUC4-transfected cells. These studies demonstrate that MUC4 overexpression leads to an enriched ovarian cancer stem cell population either directly or indirectly through HER2. In future, this study would be helpful for MUC4-directed therapy for the ovarian cancer stem cell population.

BAX-dependent mitochondrial pathway mediates the crosstalk between ferroptosis and apoptosis

Abstract: Ferroptosis is considered a distinctive form of cell death compared to other types of death such as apoptosis. It is known to result from iron-dependent accumulation of lipid peroxides rather than caspase activation. However, we reported recently that ferroptosis interplays with apoptosis. In this study, we investigated a possible mechanism of this interplay between ferroptosis and apoptosis. Results from our studies reveal that combined treatment of the ferroptotic agent erastin and the apoptotic agent TRAIL effectively disrupted mitochondrial membrane potential (ΔΨm) and subsequently promoted caspase activation. The alterations of mitochondrial membrane potential are probably due to an increase in oligomerization of BAX and its accumulation at the mitochondria during treatment with erastin and TRAIL. Interestingly, the combined treatment-promoted apoptosis was effectively inhibited in BAX-deficient HCT116 cells, but not BAK-deficient cells. These results indicate that the BAX-associated mitochondria-dependent pathway plays a pivotal role in erastin-enhanced TRAIL-induced apoptosis.

Effects of differentiation on the transcriptional regulation of the FGF-4 gene: critical roles played by a distal enhancer

Abstract: Embryonal carcinoma (EC) cells are used widely as a model system for studying the expression of developmentally regulated genes, in particular genes that are regulated at the transcriptional level when EC cells differentiate. This review focuses on the molecular mechanisms that govern the transcription of the fibroblast growth factor-4 (FGF-4) gene, which appears to be the first FGF expressed during mammalian development. Interest in this gene has increased considerably with the finding that FGF-4 is essential for mammalian embryogenesis. The FGF-4 gene has also generated considerable interest because it is inhibited at the transcriptional level when EC cells undergo differentiation and because this gene is regulated by a powerful distal enhancer located 3 kb downstream of the transcription start site in the last exon of the gene. Hence, study of the FGF-4 gene is likely to shed light on the molecular mechanisms by which distal enhancers regulate gene expression. In addition to being regulated by the downstream enhancer, the expression of this gene is influenced by a regulatory region located just upstream of the transcription start site, which contains two Sp1 motifs and a CCAAT box motif. Examination of the downstream enhancer has identified three functional cis-regulatory elements: a high mobility group (HMG) protein binding motif, an octamer binding motif, and an Sp1 motif, which are likely to bind Sox-2, Oct-3, and Sp1/Sp3, respectively, in vivo. Interestingly, Sox-2 and Oct-3 expression, like FGF-4 expression, decreases when EC cells differentiate, which suggests that the loss of these transcription factors is responsible, at least in part, for the transcriptional turn-off of the FGF-4 gene. In view of these and other findings, we present a model for the differential expression of the FGF-4 gene that includes not only the contributions of specific transcription factors, but also the contribution of chromatin structure before and after differentiation.

The MAPK Scaffold Kinase Suppressor of Ras Is Involved in ERK Activation by Stress and Proinflammatory Cytokines and Induction of Arthritis

Abstract: The MAPK ERK is required for LPS-induced TNF production by macrophages. Although the scaffold kinase suppressor of Ras (KSR)1 is required for efficient Erk activation by mitogenic stimuli, the role of KSR1 in ERK activation by inflammatory and stress stimuli is unknown. In this study, we examined the effects of KSR deficiency on ERK activation by stress stimuli and show that ERK activation by TNF, IL-1, and sorbitol is attenuated in the absence of KSR1. To determine the significance of this defect in vivo, we tested KSR-deficient mice using a passive transfer model of arthritis. We found that the induction of arthritis is impaired in the absence of KSR. Thus, KSR plays a role in ERK activation during inflammatory and stress responses both in vitro and in vivo.