Statins in tumor suppression.

Statins are HMG-CoA reductase inhibitors with important cholesterol-lowering properties. The introduction of these agents in clinical medicine has had a major impact and has changed the natural history of coronary artery disease in humans. Beyond their cholesterol-lowering properties, statins exhibit important anti-inflammatory and antitumor activities.

Acute lymphoblastic leukemia in a patient with chronic cyanoacrylate exposure.

Environmental agents have long been thought to be linked to the development of malignancies. Due to the difficulty in identifying and verifying exposures to such agents, only a few chemical compounds are clearly linked to malignancies. We report here the case of a 36-year-old man with pre-B cell acute lymphoblastic leukemia.

Regulatory effects of mammalian target of rapamycin-mediated signals in the generation of arsenic trioxide responses.

Arsenic trioxide (As(2)O(3)) is a potent inducer of apoptosis of leukemic cells in vitro and in vivo, but the mechanisms that mediate such effects are not well understood. We provide evidence that the Akt kinase is phosphorylated/activated during treatment of leukemia cells with As(2)O(3), to regulate downstream engagement of mammalian target of rapamycin (mTOR) and its effectors. Using cells with targeted disruption of both the Akt1 and Akt2 genes, we found that induction of arsenic trioxide-dependent apoptosis is strongly enhanced in the absence of these kinases, suggesting that Akt1/Akt2 are activated in a negative feedback regulatory manner, to control generation of As(2)O(3) responses.

The protein kinase C (PKC) family of proteins in cytokine signaling in hematopoiesis.

The members of the protein kinase C (PKC) family of proteins play important roles in signaling for various growth factors, cytokines, and hormones. Extensive work over the years has led to the identification of three major groups of PKC isoforms. These include the classic PKCs (PKCalpha, PKCbeta(I), PKCbeta(II), PKCgamma), the novel PKCs (PKCdelta, PKCepsilon, PKCeta, PKCmu, PKCtheta), and the atypical PKCs (PKCzeta, PKCiota/lambda).

Suppressive effects of statins on acute promyelocytic leukemia cells.

The family of statins includes pharmacologic inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase that are potent regulators of cholesterol biosynthesis. In addition to their cholesterol-lowering effects, statins inhibit cell proliferation and promote apoptosis of malignant cells in vitro, but their potential therapeutic roles in the treatment of malignancies remain to be defined. We examined the effects of statins on the growth and differentiation of acute myeloid leukemia (AML) cells.

Sanguinarine-dependent induction of apoptosis in primary effusion lymphoma cells.

Primary effusion lymphoma (PEL) is an incurable, aggressive B-cell malignancy that develops rapid resistance to conventional chemotherapy. In efforts to identify novel approaches to block proliferation of PEL cells, we found that sanguinarine, a natural compound isolated from the root plant Sanguinaria canadendid, inhibits cell proliferation and induces apoptosis in a dose-dependent manner in several PEL cell lines. Our data show that sanguinarine treatment of PEL cells results in up-regulation of death receptor 5 (DR5) expression via generation of reactive oxygen species (ROS) and causes activation of caspase-8 and truncation of Bid (tBid).

GRIM-19 associates with the serine protease HtrA2 for promoting cell death.

We have isolated a novel interferon (IFN)-retinoid regulated cell death regulatory protein genes associated with retinoid-IFN-induced mortality (GRIM)-19 earlier. To understand its mechanism of action, we have employed a yeast-two-hybrid screen and identified serine protease HtrA2 as its binding partner. GRIM-19 physically interacts with HtrA2 and augments cell death in an IFN/all-trans retinoic acid (RA)-dependent manner.

Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL-expressing cells.

Arsenic trioxide (As(2)O(3)) exhibits important antitumor activities in vitro and in vivo, but the precise mechanisms by which it induces its effects are not known. We provide evidence that during treatment of BCR-ABL-expressing cells with As(2)O(3), there is activation of a cellular pathway involving the p70 S6 kinase (p70S6K). Our data show that p70S6K is rapidly phosphorylated on Thr(421) and Ser(424) and is activated in an As(2)O(3)-inducible manner.

Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling.

The mechanisms regulating initiation of mRNA translation for the generation of protein products that mediate interferon (IFN) responses are largely unknown. We have previously shown that both Type I and II IFNs engage the mammalian target of rapamycin (mTOR), resulting in downstream phosphorylation and deactivation of the translational repressor 4E-BP1 (eIF4E-binding protein 1). In the current study, we provide direct evidence that such regulation of 4E-BP1 by IFNalpha or IFNgamma results in sequential dissociation of 4E-BP1 from eukaryotic initiation factor-4E and subsequent formation of a functional complex between eukaryotic initiation factor-4E and eukaryotic initiation factor-4G, to allow initiation of mRNA translation.

c-Src interacts with and phosphorylates RelA/p65 to promote thrombin-induced ICAM-1 expression in endothelial cells.

The procoagulant thrombin promotes polymorphonuclear leukocyte (PMN) adhesion to endothelial cells by a mechanism involving expression of intercellular adhesion molecule-1 (ICAM-1) via an NF-kappaB-dependent pathway. We now provide evidence that activation of c-Src is crucial in signaling thrombin-induced ICAM-1 expression via tyrosine phosphorylation of RelA/p65. Stimulation of human umbilical vein endothelial cells with thrombin resulted in a time-dependent activation of c-Src, with maximal activation occurring at 30 min after thrombin challenge.

Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors.

The myelodysplastic syndromes (MDSs) are collections of heterogeneous hematologic diseases characterized by refractory cytopenias as a result of ineffective hematopoiesis. Development of effective treatments has been impeded by limited insights into any unifying pathogenic pathways. We provide evidence that the p38 MAP kinase is constitutively activated or phosphorylated in MDS bone marrows.

Role of the p38 mitogen-activated protein kinase pathway in the generation of arsenic trioxide-dependent cellular responses.

Arsenic trioxide (As(2)O(3)) induces differentiation and apoptosis of leukemic cells in vitro and in vivo, but the precise mechanisms that mediate such effects are not known. In the present study, we provide evidence that the kinases MAPK kinase 3 (Mkk3) and Mkk6 are activated during treatment of leukemic cell lines with As(2)O(3) to regulate downstream engagement of the p38 mitogen-activated protein kinase. Using cells with targeted disruption of both the Mkk3 and Mkk6 genes, we show that As(2)O(3)-dependent activation of p38 is defective in the absence of Mkk3 and Mkk6, establishing that these kinases are essential for As(2)O(3)-dependent engagement of the p38 pathway.

Vaccinia virus activation of CCR5 invokes tyrosine phosphorylation signaling events that support virus replication.

Vaccinia virus, a poxvirus, produces structurally distinct forms of virions for which the immediate events following cell entry are ill-defined. We provide evidence that intracellular mature virus (IMV) enters both permissive and nonpermissive T-cell lines and that introduction of CCR5 into nonpermissive mouse fibroblasts or human primary T cells renders the cells permissive for vaccinia replication. Notably, T cells expressing CCR5 in which tyrosine 339 in the intracellular region is replaced by phenylalanine no longer support virus replication or virus-inducible activation of specific host cell signaling effectors IRS-2, Grb2, and Erk1/2.

Activation of the mitogen- and stress-activated kinase 1 by arsenic trioxide.

Arsenic trioxide (As2O3) is a potent inducer of apoptosis of leukemic cells in vitro and in vivo, but the precise mechanisms by which it mediates such effects are not well defined. We provide evidence that As2O3 induces activation of the mitogen- and stress-activated kinase 1 (MSK1) and downstream phosphorylation of its substrate, histone H3, in leukemia cell lines. Such activation requires upstream engagement of p38 MAPK, as demonstrated by experiments using pharmacological inhibitors of p38 or p38alpha knock-out cells.

Curcumin induces apoptosis via inhibition of PI3'-kinase/AKT pathway in acute T cell leukemias.

Curcumin has been shown to possess variety of biological functions including anti-tumor activity. The mechanism by which curcumin inhibit cell proliferation remains poorly understood. In the present report, we investigated the effect of curcumin on the activation of apoptotic pathway in T-cell acute lymphoblastic leukemia (T-ALL) malignant cells.

The PI3' kinase pathway in interferon signaling.

Interferons (IFNs) are pleiotropic cytokines with important immunomodulatory, antitumor, antiviral, and growth inhibitory properties. Consistent with the multiplicity of their effects, the IFNs activate several cellular cascades after they bind to their receptors. Although the Jak-Stat pathway is the most studied pathway, it appears that additional signaling cascades play roles in IFN signaling.

The p38 mitogen-activated protein kinase pathway in interferon signal transduction.

Interferons (IFNs) are cytokines that regulate a variety of biologic effects, including cellular antiviral responses, inhibition of proliferation, induction of differentiation, and immunoregulation, via different mechanisms. In order to mediate such pleiotropic effects, IFNs trigger numerous signaling events. One way for IFNs to regulate cellular functions is through activation of mitogen-activated protein (MAP) kinases.

Role of the p38 mitogen-activated protein kinase pathway in cytokine-mediated hematopoietic suppression in myelodysplastic syndromes.

The p38 mitogen-activated protein kinase (MAPK) pathway is activated by IFNs and other cytokines to mediate signals for important cellular functions, including transcriptional regulation and apoptosis. We examined the role of the p38 pathway in the generation of the effects of myelosuppressive cytokines on human hematopoiesis. Pharmacologic inhibition of p38 using BIX-01208 resulted in reversal of IFN-, tumor necrosis factor-alpha (TNF-alpha)-, and transforming growth factor-beta (TGF-beta)-mediated suppression of human erythroid (blast-forming unit-erythroid) and myeloid (granulocyte-macrophage colony-forming unit) colony formation, consistent with a key role for p38 in the generation of myelosuppressive signals by different cytokines.

Curcumin suppresses growth and induces apoptosis in primary effusion lymphoma.

The mechanisms that regulate induction of the antiapoptotic state and mitogenic signals in primary effusion lymphoma (PEL) are not well known. In efforts to identify novel approaches to block the proliferation of PEL cells, we found that curcumin (diferuloylmethane), a natural compound isolated from the plant Curcuma Ionga, inhibits cell proliferation and induces apoptosis in a dose dependent manner in several PEL cell lines. Such effects of curcumin appear to result from suppression of the constitutively active STAT3 through inhibition of Janus kinase 1 (JAK1).

Mitogen-activated protein kinase pathways in interferon signaling.

There is recent evidence that in addition to the classic JAK/STAT pathways, mitogen-activated proteins (MAP) kinase pathways play important roles in Type I interferon signaling and the generation of interferon responses. In particular, the p38 MAP kinase cascade exerts positive regulatory roles on transciptional activation of interferon-sensitive genes (ISGs) and the induction of the antiproliferative and antiviral properties of interferons. In this chapter, methodologies to detect activation of p38 and various upstream and downstream effectors are provided.

Mitochondrial reactive oxygen species activation of p38 mitogen-activated protein kinase is required for hypoxia signaling.

Mammalian cells have the ability to sense low oxygen levels (hypoxia). An adaptive response to hypoxia involves the induction of the transcription factor hypoxia-inducible factor 1 (HIF-1). The intracellular signaling pathways that regulate HIF-1 activation during hypoxia remain unknown.