Diffuse large B-cell lymphoma and red cell autoimmunity: clinical role and pathogenesis.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of B-cell non-Hodgkin lymphoma (B-NHL) with significant morbidity and mortality despite advancements in treatment. Lymphoma and autoimmune disease both result from breakdowns in normal cell regulatory pathways, and epidemiological studies have confirmed both that B-NHL is more likely to develop in the setting of autoimmune diseases and vice versa. Red cell immunity, as evidenced by direct antiglobulin test (DAT) positivity, has been linked to DLBCL and more recently the pathogenic causes of this association have begun to be better understood using molecular techniques.

Plasma cells arise from differentiation of clonal lymphocytes and secrete IgM in Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is characterized by bone marrow infiltration with malignant lymphoplasmacytic cells (LPCs), a smaller population of plasma cells (PCs), and hypersecretion of IgM monoclonal protein. Here, we show that CD45, CD38, and CD138 PCs and CD45, CD38, CD138, CD19, and CD20 LPCs carry a heterozygous L265P mutation in the Toll-like receptor signaling adaptor MYD88. Both PCs and LPCs express the same auto-reactive IgHV sequences, suggesting a similar clonal origin and role for auto-antigens in WM cell survival.

α-Actinin 4 potentiates nuclear factor κ-light-chain-enhancer of activated B-cell (NF-κB) activity in podocytes independent of its cytoplasmic actin binding function.

Glomerular podocytes are highly specialized terminally differentiated cells that act as a filtration barrier in the kidney. Mutations in the actin-binding protein, α-actinin 4 (ACTN4), are linked to focal segmental glomerulosclerosis (FSGS), a chronic kidney disease characterized by proteinuria. Aberrant activation of NF-κB pathway in podocytes is implicated in glomerular diseases including proteinuria.

Control of antioxidative response by the tumor suppressor protein PML through regulating Nrf2 activity.

Oxidative stress is a consequence of an imbalance between reactive oxygen species (ROS) production and the ability of the cytoprotective system to detoxify the reactive intermediates. The tumor suppressor promyelocytic leukemia protein (PML) functions as a stress sensor. Loss of PML results in impaired mitochondrial complex II activity, increased ROS, and subsequent activation of nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidative pathway.

Monensin, a polyether ionophore antibiotic, overcomes TRAIL resistance in glioma cells via endoplasmic reticulum stress, DR5 upregulation and c-FLIP downregulation.

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is preferentially cytotoxic to cancer cells over normal cells. However, many cancer cells, including malignant glioma cells, tend to be resistant to TRAIL. Monensin (a polyether ionophore antibiotic that is widely used in veterinary medicine) and salinomycin (a compound that is structurally related to monensin and shows cancer stem cell-inhibiting activity) are currently recognized as anticancer drug candidates.

Rottlerin induces apoptosis of HT29 colon carcinoma cells through NAG-1 upregulation via an ERK and p38 MAPK-dependent and PKC δ-independent mechanism.

Rottlerin, a selective inhibitor of novel isoforms of protein kinase C δ (PKC δ), has been shown to exert multiple effects on cancer cells, including inhibition of cell proliferation and migration. However, the molecular mechanisms responsible for these effects are not fully understood. We found that rottlerin dramatically induced non-steroidal anti-inflammatory drug activated gene-1 (NAG-1) expression in both p53 wild-type and p53-null cancer cell lines, suggesting that NAG-1 upregulation is a common response to rottlerin that occurs independently of p53 in multiple cell lines.

Mitogen-activated protein kinase extracellular signal-regulated kinase 2 phosphorylates and promotes Pin1 protein-dependent promyelocytic leukemia protein turnover.

The promyelocytic leukemia (PML) protein is a tumor suppressor that has an important role in several cellular processes, including apoptosis, viral infection, DNA damage repair, cell cycle regulation, and senescence. PML is an essential component of sub-nuclear structures called PML nuclear bodies (NBs). Our laboratory has previously demonstrated that the peptidyl-prolyl cis-trans isomerase, Pin1, binds and targets PML for degradation in a phosphorylation-dependent manner.

Superoxide anion and proteasomal dysfunction contribute to curcumin-induced paraptosis of malignant breast cancer cells.

Curcumin is considered a pharmacologically safe agent that may be useful in cancer chemoprevention and therapy. Here, we show for the first time that curcumin effectively induces paraptosis in malignant breast cancer cell lines, including MDA-MB-435S, MDA-MB-231, and Hs578T cells, by promoting vacuolation that results from swelling and fusion of mitochondria and/or the endoplasmic reticulum (ER). Inhibition of protein synthesis by cycloheximide blocked curcumin-induced vacuolation and subsequent cell death, indicating that protein synthesis is required for this process.

Rottlerin induces heme oxygenase-1 (HO-1) up-regulation through reactive oxygen species (ROS) dependent and PKC delta-independent pathway in human colon cancer HT29 cells.

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated by its substrate heme and diverse stimuli. The induction of HO-1 gene expression is one of the important events in cellular response to pro-oxidative and pro-inflammatory insults. In this study, the effect of rottlerin, a putative PKC delta inhibitor, on HO-1 expression in HT29 human colon cancer cells was investigated.

Curcumin inhibits phorbol myristate acetate (PMA)-induced MCP-1 expression by inhibiting ERK and NF-kappaB transcriptional activity.

Monocyte chemoattractant protein-1 (MCP-1) is a potent mediator of macrophage migration and therefore, plays an essential role in early events of inflammation. In the present study, we show the protein kinase C activator, phorbol myristate acetate (PMA), potently induced mRNA expression and secretion of the C-C chemokine MCP-1 in U937 cells. We found that curcumin, a natural biologically active compound extracted from rhizomes of Curcuma species, significantly inhibited the PMA-induced increase in MCP-1 expression and secretion.

Interleukin-1beta promotes the expression of monocyte chemoattractant protein-1 in human aorta smooth muscle cells via multiple signaling pathways.

Monocyte chemoattractant protein-1 (MCP1) plays a key role in monocyte/macrophage infiltration to the sub-endothelial space of the blood vessel wall, which is a critical initial step in atherosclerosis. In this study, we examined the intracellular signaling pathway of IL-1beta-induced MCP1 expression using various chemical inhibitors. The pretreatment of a phosphatidylcholine (PC)-specific PLC (PC-PLC) inhibitor (D609), PKC inhibitors, or an NF-kapaB inhibitor completely suppressed the IL-1beta-induced MCP1 expression through blocking NF-gammaB translocation to the nucleus.

Rottlerin induces apoptosis via death receptor 5 (DR5) upregulation through CHOP-dependent and PKC delta-independent mechanism in human malignant tumor cells.

Rottlerin has been shown to induce antiproliferation and apoptosis of human cancer cell lines. In this study, we demonstrate a novel mechanism of rottlerin-induced apoptosis via death receptor (DR) 5 upregulation. We found that treatment with rottlerin significantly induces DR5 expression both at its messenger RNA and protein levels.

Quercetin sensitizes human hepatoma cells to TRAIL-induced apoptosis via Sp1-mediated DR5 up-regulation and proteasome-mediated c-FLIPS down-regulation.

This study demonstrates that combined treatment with subtoxic doses of quercetin (3',3',4',5,7-pentahydroxyflavone), a flavonoid found in many fruits and vegetables, plus tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rapid apoptosis in TRAIL-resistant hepatocellular carcinoma (HCC) cells. Effective induction of apoptosis by the combined treatment with quercetin and TRAIL was not blocked by overexpression of Bcl-xL, which is known to confer resistance to various chemotherapeutic agents. These results suggest that this combined treatment may provide an attractive strategy for treating resistant HCCs.

Rottlerin induces pro-apoptotic endoplasmic reticulum stress through the protein kinase C-delta-independent pathway in human colon cancer cells.

Rottlerin, a compound reported to be a PKC delta-selective inhibitor, has been shown to induce growth arrest or apoptosis of human cancer cell lines. In our study, rottlerin dose-dependently induced apoptotic cell death in colon carcinoma cells. Treatment of HT29 human colon carcinoma cells with rottlerin was found to induce a number of signature ER stress markers; phosphorylation of eukaryotic initiation factor-2alpha (eIF-2alpha), ER stress-specific XBP1 splicing, and up-regulation of glucose-regulated protein (GRP)-78 and CCAAT/enhancer-binding protein-homologous protein (CHOP).

Resveratrol induces pro-apoptotic endoplasmic reticulum stress in human colon cancer cells.

Resveratrol (3,4',5 tri-hydroxystilbene), a naturally occurring polyphenolic compound highly enriched in grapes and red wine, has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. Resveratrol-induced dose-dependent apoptotic cell death in colon carcinoma cells, was measured by FACS analysis. Treatment of HT29 human colon carcinoma cells with resveratrol was found to induce a number of signature ER stress markers; phosphorylation of eukaryotic initiation factor-2alpha (eIF-2alpha), ER stress-specific XBP1 splicing and CCAAT/enhancer-binding protein-homologous protein (CHOP).

Expression of cyclin D3 through Sp1 sites by histone deacetylase inhibitors is mediated with protein kinase C-delta (PKC-delta) signal pathway.

The histone deacetylase (HDAC) inhibitors are an exciting new class of drugs that are targeted as anti-cancer agents. These compounds can induce growth arrest, apoptosis, and/or terminal differentiation in a variety of cancers. The inhibition of HDACs shifts toward hyper-acetylation, thereby driving transcriptional activation.

ESE-3 transcription factor is involved in the expression of death receptor (DR)-5 through putative Ets sites.

The death receptor 5 (DR-5), a receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), is critical for TRAIL-mediated apoptosis in various tumor cells. The ESE-3, a member of Ets transcription factors, regulates the expression of a variety of cellular genes by binding to purine-rich GGAA/T core sequence in cooperation with other transcription factors and co-factors. In this study, we demonstrate for the first time that ESE-3 regulates DR-5 expression through Ets binding sequences on the DR-5 promoter.

Differential inhibitory effects of baicalein and baicalin on LPS-induced cyclooxygenase-2 expression through inhibition of C/EBPbeta DNA-binding activity.

To evaluate the possible mechanisms responsible for the anti-inflammatory effects of baicalein or baicalin, lipopolysaccharide (LPS)-induced inflammatory responses in cultured Raw 264.7 cells were studied. In the present study, baicalein and baicalin, a flavonoid present in the root of Scutellaria baicalensis Georgi, were examined for their effects on LPS-induced cyclooxygenase-2 (COX-2) gene expression in Raw 264.

Quercetin arrests G2/M phase and induces caspase-dependent cell death in U937 cells.

Quercetin, a natural product derived from grapes, has been shown to prevent carcinogenesis in murine models. We report here that quercetin induces anti-proliferation and arrests G2/M phase in U937 cells. The G2/M phase accumulation was accompanied by an increase in the level of the cyclin B.

Inhibitory modulation of ATP-sensitive potassium channels by gallate-ester moiety of (-)-epigallocatechin-3-gallate.

(-)-Epigallocatechin-3-gallate (EGCG), a major polyphenolic substance found in green tea, is well recognized to be beneficial for human health. However, it is still controversial as to what dose of this compound is indeed good for human health. Though some recent studies have interestingly reported various beneficial effects of EGCG in cell culture system, however, plasma levels of EGCG attainable by oral regular intake in humans are normally in nanomolar range.

Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5).

Curcumin exhibits anti-inflammatory and antitumor activities. Although its functional mechanism has not been elucidated so far, numerous studies have shown that curcumin induces apoptosis in cancer cells. In the present study, we show that subtoxic concentrations of curcumin sensitize human renal cancer cells to the tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis.

Activation of human cancer/testis antigen gene, XAGE-1, in tumor cells is correlated with CpG island hypomethylation.

Expression of the XAGE-1 antigen is restricted to germ cells of the testis and a variety of neoplastic tissues. To date, the molecular mechanism for regulating expression of this cancer/testis antigen gene has been unknown. To evaluate methylation as a potential mechanism for regulating expression of this gene, we first correlated gene methylation status (measured by sequencing of bisulfide-modified DNA and COBRA) to expression of XAGE-1 mRNA in normal and cancerous cells.

8-Hydroxyquinoline inhibits iNOS expression and nitric oxide production by down-regulating LPS-induced activity of NF-kappaB and C/EBPbeta in Raw 264.7 cells.

In activated macrophage, large amounts of nitric oxide (NO) are generated by inducible nitric oxide synthase (iNOS), resulting in acute or chronic inflammatory disorders. In Raw 264.7 cells stimulated with lipopolysaccharide (LPS) to mimic inflammation, 8-hydroxyquinoline (8HQ) inhibited the LPS-induced expression of both iNOS protein and mRNA in a parallel dose-dependent manner.