Begell House Inc.
Onco Therapeutics
OT
2694-4642
1
3
2010
Cross-Regulation Between WNT and NF-κB Signaling Pathways
155-181
10.1615/ForumImmunDisTher.v1.i3.10
Qiang
Du
Department of Surgery, T.E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
David
Geller
University of Pittsburgh
Wnt signaling pathway
NF-κB signaling pathway
cross-regulation
β-catenin
Cross-regulation between the Wnt and nuclear factor (NF)-κB signaling pathways has emerged as an important area for the regulation of a diverse array of genes and pathways active in chronic inflammation, immunity, development, and tumorigenesis. The ligands, kinases, transcription factors, and products of their target gene expression are involved in cross-regulation of these two signaling pathways. Both β-catenin and NF-κB activate inducible nitric oxide synthase (iNOS) gene expression; however, β-catenin also exerts an inhibitory effect on NF-κB-mediated transcriptional activation, including iNOS. The recent discovery of functional cross-regulation between these two pathways has shown complex roles for Wnt/β-catenin and NF-κB signaling in the pathogenesis of certain cancers and other diseases. This review focuses on the molecular mechanisms of cross-regulation between Wnt/β-catenin and NF-κB signaling pathways in cancer cells.
Inducible Nitric Oxide Synthase/ Cyclooxygenase-2 Pathway Interaction: A Good Molecular Target for Cancer Treatment
183-204
10.1615/ForumImmunDisTher.v1.i3.20
Emanuela
Masini
Department of Preclinical and Clinical Pharmacology, Medical School, University of Florence, Florence
Fabio
Cianchi
Department of Medical and Surgical Critical Care, Medical School, University of Florence, Florence
nitric oxide synthase
cyclooxygenase-2
prostaglandins
cancer
angiogenesis
An increase in the expression and activity of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) has been shown in several types of human tumors. A large body of evidence has demonstrated that these two enzymes are involved in tumor progression through several molecular mechanisms, such as promotion of tumor cell proliferation, inhibition of apoptosis, and stimulation of angiogenesis. iNOS and COX-2 share a number of similarities in terms of pathophysiological phenomena, and are often co-expressed in cancer tissues. The product of iNOS, nitric oxide (NO), has been demonstrated to modulate COX-2 expression and prostaglandin production in both inflammatory and tumor experimental models. Cyclic GMP and peroxynitrite, the coupling product of NO and O2−, appear to be the most important pathways by which NO may regulate COX-2 expression. We have recently shown that both NO- and COX-2-related angiogenesis are mediated by an increase in vascular endothelial growth factor (VEGF) production in colorectal cancer. We also provided evidence that NO can stimulate COX activity, and that its pro-angiogenic effect is mainly mediated by COX-2-related prostaglandin E2 (PGE2) production. The purpose of this review is to summarize experimental data on the molecular mechanisms underlying iNOS-COX-2 cross-talk and investigate the pathophysiological significance of this interaction in cancer. Given the availability of highly selective inhibitors of both iNOS and COX-2, dual inhibition of these enzymes appears to be a promising therapeutic tool in the treatment of various types of human cancers possibly by producing a synergistic anti-tumor effect.
Broad-Spectrum Anti-Cancer Activity of O2-Arylated Diazeniumdiolates
205-218
10.1615/ForumImmunDisTher.v1.i3.30
Larry K.
Keefer
Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
nitric oxide
JS-K
arylating agents
glutathione
PABA/NO
O2-(2,4-Dinitrophenyl) l-[(4-ethoxycarbonyl)piperazin-l-yl]diazen-l-ium-l,2-diolate (JS-K) and O2-{2,4-dinitro-5-[4-(N-methylammo)be nzoyloxy]phenyl} l-(N,N-dimethylamino)diazen-l-ium-l,2-diolate (PABA/NO) are O2-arylated diazeniumdiolates that have shown promising in vivo activity in a variety of rodent cancer models, including prostate cancer, leukemia, liver cancer, multiple myeloma, and ovarian cancer. This compound class was designed to be activated for anti-cancer effects by glutathione-S-transferase (GST)-induced release of cytotoxic nitric oxide (NO), but mechanistic studies have implicated a variety of pathways, some GST/NO-related, some not. Current work is focused on improving formulations and other drug development activities, as well as exploring possible new applications of these agents and their analogs. The selectivity of these drugs for attacking tumors while exhibiting little toxicity toward normal tissues suggests considerable promise for the treatment of various tumor types.
Inhibition of Snail-induced Epithelial-Mesenchymal Transition and Induction of the Tumor Metastasis Suppressor Gene Raf-1 Kinase Inhibitor Protein (RKIP) by DETANONOate
219-230
10.1615/ForumImmunDisTher.v1.i3.40
Stavroula
Baritaki
Center for Systems Biomedicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
prostate cancer
metastasis
NF-κB
Snail
Raf-1 kinase inhibitor protein
RKIP
nitric oxide
Tumor metastasis initiates through the epithelial to mesenchymal transition (EMT) process. Unraveling the underlying molecular mechanisms of EMT should identify novel targets for therapeutic intervention. Nitric oxide (NO) sensitizes resistant tumors to apoptosis through inhibition of the constitutively activated nuclear factor (NF)-κB signaling. Since NF-κB hyperactivation is associated with tumor metastasis via regulation of EMT, we hypothesized that NF-κB inhibition by NO should suppress EMT. We demonstrate that treatment of the metastatic human prostate cancer cell lines DU145 and PC-3 with (Z)-l-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-l-ium-l,2-diolate (DETANONOate) inhibits significantly the constitutive NF-κB activity through p50 S-nitrosylation and the expression of the mesenchymal markers vimentin and fibronectin, where it augments the expression of the epithelial markers E-cad-herin and cytokeratin 18. Also, the NO-treated cells had decreased migratory and invasive properties. We further show that NO-mediated NF-κB inhibition results in downstream inhibition of its transcriptional target, Snail (SNAI1), a known EMT inducer. Snail inhibition, in turn, triggers the induction of the metastasis suppressor gene products Raf-1 kinase inhibitor protein (RKIP) and E-cadherin, whose transcriptions are negatively regulated by Snail. Thus, RKIP induction further suppresses NF-κB and consequently inhibits EMT. The above findings were corroborated by cell transfections with Snail siRNA and RKIP overexpression vectors and were validated in vivo in mice bearing PC-3 xenografts that were treated with DETANONOate. These findings establish for the first time the role of NO in the inhibition of EMT via dysregulation of the NF-κB-Snail-RKIP circuitry, and suggest the potential therapeutic application of NO donors in the regulation of metastasis.