Deguelin Action Involves c-Met and EGFR Signaling Pathways in Triple Negative Breast Cancer Cells

Background

Treatment of breast cancer patients with antiestrogens and aromatase inhibitor(s) or Herceptin have shown significant success in steroid receptor positive or Her-2+ breast cancers respectively. However, choice of treatments for breast cancer patients with negative status for estrogen, progesterone receptors and HER2/neu is limited. As a result, search for appropriate therapy regimen for these triple negative breast cancers (TNBC) has become a major focus of investigations for many laboratories. Recently, Deguelin, a natural product isolated from African plant Mundulea sericea (Leguminossae) has shown both antiproliferative actions in various cancers including breast as well as chemoprenventive activity against carcinogen induced experimental cancers. In this report we evaluated efficacy and mechanism of action of Deguelin in triple negative breast cancer cell lines.

Methods/Findings

In vitro, Deguelin in a dose and time dependent manner inhibited the growth of MDA-MB-231, MDA-MB-468, BT-549 and BT-20 cells. Deguelin (2 or 4 mg/kg body weight), when injected intraperitoneally, reduced the in vivo tumor growth of MDA-MB-231 cells transplanted subcutaneously in athymic mice. Moreover it was nontoxic as evident from daily observations on mobility, food and water consumption and comparison of bodyweight and other visceral organ weights with those in control animals at the termination of the study. The western blot analyses and immunostaining studies indicated that the deguelin effects may be mediated through EGFR-PAKT/c-Met p-ERK and NF-κB by down regulating their downstream targets such as p-STAT3, c-Myc, Survivin.

Conclusion/Significance

These results suggest that Deguelin may have a significant therapeutic value for the treatment of TNBC patients.     

Progression of fibrosis during chronic hepatitis C is associated with rapid virus evolution

Hepatic fibrosis is the primary mediator of disease due to chronic infection with hepatitis C virus (HCV). HCV exists as a quasispecies in each infected individual, and longitudinal viral sequence changes may reveal viral dynamics and the selection pressures applied by the host immune system. Thus, we hypothesized that patterns of sequence change might reveal the immunopathogenesis of fibrosis progression. We tested this hypothesis by studying individuals enrolled in a prospective study of chronic HCV-related hepatic fibrosis with little or no fibrosis at first biopsy (stage 0 or 1) and a second planned liver biopsy sample obtained 4 years later. Serum was obtained from five individuals with fast progression (FP; defined as a >2-stage change between visits) and 10 carefully matched individuals with slow progression (SP; defined as a <2-stage change between visits). We sequenced multiple cloned hemigenomic cDNAs from each person spanning six genes (core through NS3). Phylogenetic analysis revealed temporal shifts in phylogenetic clustering over time, suggesting frequent quasispecies replacement rather than simple diversification. In addition, mixed infections were detected in three subjects, with coexistence in two subjects (one FP, one SP) of subtypes 1a and 1b throughout the 4-year biopsy interval. Subjects with FP had a higher rate of evolution than subjects with SP, with a preponderance of synonymous changes, suggesting purifying selection, except in hypervariable region 1, where positive selection pressure is frequently detected. Thus, in a small but carefully matched cohort we found evidence for rapid neutral evolution of HCV in persons with rapid progression of hepatic fibrosis, suggesting higher turnover of infected cells.     

TREM-1 Is Induced in Tumor Associated Macrophages by Cyclo-Oxygenase Pathway in Human Non-Small Cell Lung Cancer

It is increasingly recognized that the tumor microenvironment plays a critical role in the initiation and progression of lung cancer. In particular interaction of cancer cells, macrophages, and inflammatory response in the tumor microenvironment has been shown to facilitate cancer cell invasion and metastasis. The specific molecular pathways in macrophages that immunoedit tumor growth are not well defined. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a member of the super immunoglobulin family expressed on a select group of myeloid cells mainly monocyte/macrophages. Recent studies suggest that expression of TREM-1 in tumors may predict cancer aggressiveness and disease outcomes in liver and lung cancer however the mechanism of TREM-1 expression in the setting of cancer is not defined. In this study we demonstrate that tumor tissue from patients with non-small cell lung cancer show an increased expression of TREM-1 and PGE₂. Immunohistochemistry and immunofluorescence confirmed that the expression of TREM-1 was selectively seen in CD68 positive macrophages. By employing an in vitro model we confirmed that expression of TREM-1 is increased in macrophages that are co-cultured with human lung cancer cells. Studies with COX-2 inhibitors and siCOX-2 showed that expression of TREM-1 in macrophages in tumor microenvironment is dependent on COX-2 signaling. These studies for the first time define a link between tumor COX-2 induction, PGE₂ production and expression of TREM-1 in macrophages in tumor microenvironment and suggest that TREM-1 might be a novel target for tumor immunomodulation.     

Beneficial effects of carvedilol as a concomitant therapy to angiotensin-converting enzyme inhibitor in patients with ischemic left ventricular systolic dysfunction

Studies are scant on the effects of short-term carvedilol treatment as an adjuvant to angiotensin-converting enzyme (ACE) inhibitor in patients with left ventricular (LV) systolic dysfunction. The objective of this study was to find the effects of short-term treatment of carvedilol on patients with ischemic LV systolic dysfunction (defined as LV ejection fraction (LVEF) 相似文献   

Profiling of cellulose content in Indian seaweed species

Cellulose contents were estimated in 12 seaweed samples belonging to different families e.g. red, brown and green, growing in Indian waters. Each cellulose sample was fractionated to yield alpha (α) and beta (β) celluloses. Characterization was done using various analytical tools and results were validated by comparison with those of the cellulose obtained from Whatman filter paper No. 4. The greatest yields of cellulose (crude), α- and β-cellulose were obtained from Gelidiella acerosa (13.65%), Chamaedoris auriculata (9.0%) and G. acerosa (3.10%). G. acerosa was also found to contain relatively high amount of α-cellulose (8.19%). The lowest cellulose contents were recorded from Kappaphycus alvarezii (2.00%) and Sarconema scinaioides (2.1%), while the latter contained the lowest α-, and β-celluloses (1.0% and 0.30%, respectively). It appears that agarophytic and alginophytic algae contain high cellulose and α-cellulose contents, while the carrageenophyte contains low cellulose. The brown algae, in general contain high cellulose as well as α- and β-celluloses.     

A trimeric DNA polymerase complex increases the native replication processivity

DNA polymerases are essential enzymes in all domains of life for both DNA replication and repair. The primary DNA replication polymerase from Sulfolobus solfataricus (SsoDpo1) has been shown previously to provide the necessary polymerization speed and exonuclease activity to replicate the genome accurately. We find that this polymerase is able to physically associate with itself to form a trimer and that this complex is stabilized in the presence of DNA. Analytical gel filtration and electrophoretic mobility shift assays establish that initially a single DNA polymerase binds to DNA followed by the cooperative binding of two additional molecules of the polymerase at higher concentrations of the enzyme. Protein chemical crosslinking experiments show that these are specific polymerase–polymerase interactions and not just separate binding events along DNA. Isothermal titration calorimetry and fluorescence anisotropy experiments corroborate these findings and show a stoichiometry where three polymerases are bound to a single DNA substrate. The trimeric polymerase complex significantly increases both the DNA synthesis rate and the processivity of SsoDpo1. Taken together, these results suggest the presence of a trimeric DNA polymerase complex that is able to synthesize long DNA strands more efficiently than the monomeric form.     

Expression signature of IFN/STAT1 signaling genes predicts poor survival outcome in glioblastoma multiforme in a subtype-specific manner

Previous reports have implicated an induction of genes in IFN/STAT1 (Interferon/STAT1) signaling in radiation resistant and prosurvival tumor phenotypes in a number of cancer cell lines, and we have hypothesized that upregulation of these genes may be predictive of poor survival outcome and/or treatment response in Glioblastoma Multiforme (GBM) patients. We have developed a list of 8 genes related to IFN/STAT1 that we hypothesize to be predictive of poor survival in GBM patients. Our working hypothesis that over-expression of this gene signature predicts poor survival outcome in GBM patients was confirmed, and in addition, it was demonstrated that the survival model was highly subtype-dependent, with strong dependence in the Proneural subtype and no detected dependence in the Classical and Mesenchymal subtypes. We developed a specific multi-gene survival model for the Proneural subtype in the TCGA (the Cancer Genome Atlas) discovery set which we have validated in the TCGA validation set. In addition, we have performed network analysis in the form of Bayesian Network discovery and Ingenuity Pathway Analysis to further dissect the underlying biology of this gene signature in the etiology of GBM. We theorize that the strong predictive value of the IFN/STAT1 gene signature in the Proneural subtype may be due to chemotherapy and/or radiation resistance induced through prolonged constitutive signaling of these genes during the course of the illness. The results of this study have implications both for better prediction models for survival outcome in GBM and for improved understanding of the underlying subtype-specific molecular mechanisms for GBM tumor progression and treatment response.