Serpine1 Mediates Induced Insulin Secretion in the Pancreatic Beta Cell Line MIN6.

Periodontitis is an inflammatory disease resulting in destruction of gingiva and alveolar bone caused by an exuberant host immunological response to periodontal pathogens. Results from a number of epidemiological studies indicate a close association between diabetes and periodontitis. Results from cross-sectional studies indicate that subjects with periodontitis have a higher odds ratio of developing insulin resistance (IR).

Porphyromonas gingivalis lipopolysaccharide upregulates insulin secretion from pancreatic β cell line MIN6.

Background: A close association between periodontitis and diabetes has been demonstrated in human cross-sectional studies, but an exact relationship between periodontitis and prediabetes has not been established. Previous studies using animal model systems consistently have shown that hyperinsulinemia occurs in animals with periodontitis compared to animals with healthy periodontium (while maintaining normoglycemia). Because bacterial lipopolysaccharide (LPS) plays an important role in the pathogenesis of periodontitis, we hypothesized that LPS may stimulate insulin secretion through a direct effect on β cell function.

DDB2 suppresses epithelial-to-mesenchymal transition in colon cancer.

Colon cancer is one of the deadliest cancers worldwide because of its metastasis to other essential organs. Metastasis of colon cancer involves a complex set of events, including epithelial-to-mesenchymal transition (EMT) that increases invasiveness of the tumor cells. Here, we show that the xeroderma pigmentosum group E (XPE) gene product, damaged DNA-binding protein (DDB)-2, is downregulated in high-grade colon cancers, and it plays a dominant role in the suppression of EMT of the colon cancer cells.

Nucleophosmin interacts with FOXM1 and modulates the level and localization of FOXM1 in human cancer cells.

Using mass spectrometric analysis we found that oncogenic transcription factor FOXM1 that is overexpressed in a majority of human cancers interacts with multifunctional protein NPM, which is also overexpressed in a variety of human tumors. Coimmunoprecipitation and glutathione S-transferase pull-down experiments demonstrated that NPM forms a complex with FOXM1 and also identified the regions responsible for their interaction. Immunofluorescence microscopy confirmed the interaction between FOXM1 and NPM in cancer and immortal cells.

Proteasome inhibitory activity of thiazole antibiotics.

Thiopeptides are sulfur containing highly modified macrocyclic antibiotics with a central pyridine/tetrapyridine/dehydropiperidine ring with up to three thiazole substituents on positions 2, 3 and 6. Thiazole antibiotics with central pyridine nucleus have a macrocyclic loop connecting thiazole rings at position 2 and 3 described as ring A. In addition antibiotics with central tetrahydropyridine nucleus have a quinaldic acid macrocycle also connected to thiazole on position 2 described as ring B.

ARC synergizes with ABT-737 to induce apoptosis in human cancer cells.

Previously, we reported that the nucleoside analogue/transcriptional inhibitor ARC (4-amino-6-hydrazino-7-beta-D-ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide) was able to induce p53-independent apoptosis in multiple cancer cell lines of different origins. This occurred, at least in part, by the suppression of short-lived, prosurvival member of the Bcl-2 family, Mcl-1. In contrast, we show here that treatment of human cancer cells with the pan-Bcl-2 inhibitor ABT-737 alone led to upregulation of Mcl-1 protein expression.

FoxM1 is a general target for proteasome inhibitors.

Proteasome inhibitors are currently in the clinic or in clinical trials, but the mechanism of their anticancer activity is not completely understood. The oncogenic transcription factor FoxM1 is one of the most overexpressed genes in human tumors, while its expression is usually halted in normal non-proliferating cells. Previously, we established that thiazole antibiotics Siomycin A and thiostrepton inhibit FoxM1 and induce apoptosis in human cancer cells.

Thiazole antibiotics target FoxM1 and induce apoptosis in human cancer cells.

Forkhead box M1 (FoxM1) oncogenic transcription factor represents an attractive therapeutic target in the fight against cancer, because it is overexpressed in a majority of human tumors. Recently, using a cell-based assay system we identified thiazole antibiotic Siomycin A as an inhibitor of FoxM1 transcriptional activity. Here, we report that structurally similar thiazole antibiotic, thiostrepton also inhibits the transcriptional activity of FoxM1.

Novel anticancer compounds induce apoptosis in melanoma cells.

We previously described the identification of a nucleoside analog transcriptional inhibitor ARC (4-amino-6-hydrazino-7-beta-D-ribofuranosyl-7H-Pyrrolo[2,3-d]-pyrimidine-5-carboxamide) and FoxM1 inhibitor, thiazole antibiotic Siomycin A that were able to induce apoptosis in cancer cell lines of different origin. Here, we report the characterization of these drugs on a panel of melanoma cell lines. We found that in contrast to the common anti-melanoma drug dacarbazine (DTIC), ARC and thiazole antibiotics, Siomycin A and thiostrepton, efficiently inhibited growth and induced cell death in melanoma cell lines in low concentrations.

Differential sensitivity of human colon cancer cell lines to the nucleoside analogs ARC and DRB.

Recently, we identified a nucleoside analog named ARC (4-amino-6-hydrazino-7-beta-D-ribofuranosyl-7H-Pyrrolo[2,3-d]pyrimidine-5-carboxamide), which has the properties of a general transcriptional inhibitor. Here, we report the characterization of ARC on a panel of colorectal cancer (CRC) cell lines. Cell death induced by ARC in CRC cells was accompanied by caspase-3 cleavage and correlated with the downregulation of antiapoptotic proteins, survivin and Mcl-1 and with the inhibition of Akt phosphorylation.

Identification of a chemical inhibitor of the oncogenic transcription factor forkhead box M1.

The oncogenic transcription factor forkhead box M1 (FoxM1) is overexpressed in a number of different carcinomas, whereas its expression is turned off in terminally differentiated cells. For this reason, FoxM1 is an attractive target for therapeutic intervention in cancer treatment. As a first step toward realizing this goal, in this study, using a high-throughput, cell-based assay system, we screened for and isolated the antibiotic thiazole compound Siomycin A as an inhibitor of FoxM1.

Tumor cell resistance to DNA topoisomerase II inhibitors: new developments.

DNA topoisomerases are critical enzymes involved in replication, transcription, chromatin assembly and other aspects of DNA metabolism. They are also the targets of important anticancer drugs. The type II topoisomerases are specific targets of drug classes that comprise complex-stabilizing (epipodophyllotoxins, anthracyclines) and catalytic (merbarone, bisdioxopiperazines) inhibitors.