cGMP signaling as a target for the prevention and treatment of breast cancer

Windham, Perrin F; Tinsley, Heather N.

doi:10.1016/j.semcancer.2014.06.006

Cited by 28 publications

(27 citation statements)

References 49 publications

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“…Finally and strikingly, the existing seven MGCs—ANF-RGC, CNP-RGC, STa-RGC, ROS-GC1, ROS-GC2, ONE-GC, GC-GC—in a specific fashion, by synthesizing cellular second messenger cyclic GMP, are linked with the physiological processes of blood pressure regulation, cellular growth, sensory transductions, neural plasticity, memory, temperature sensing (reviewed in Sharma et al, 2016) and, with tumor suppression (reviewed in Steinbrecher and Cohen, 2011; Windham and Tinsley, 2015). This study demonstrates that all these functions converge to a common site, CCD, which through a unified signal transduction mode, control these activities.…”

Section: Resultsmentioning

confidence: 99%

Membrane Guanylate Cyclase catalytic Subdomain: Structure and Linkage with Calcium Sensors and Bicarbonate

Ravichandran

Duda

Pertzev

et al. 2017

Front. Mol. Neurosci.

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Membrane guanylate cyclase (MGC) is a ubiquitous multi-switching cyclic GMP generating signaling machine linked with countless physiological processes. In mammals it is encoded by seven distinct homologous genes. It is a single transmembrane spanning multi-modular protein; composed of integrated blocks and existing in homo-dimeric form. Its core catalytic domain (CCD) module is a common transduction center where all incoming signals are translated into the production of cyclic GMP, a cellular signal second messenger. Crystal structure of the MGC’s CCD does not exist and its precise identity is ill-defined. Here, we define it at a sub-molecular level for the phototransduction-linked MGC, the rod outer segment guanylate cyclase type 1, ROS-GC1. (1) The CCD is a conserved 145-residue structural unit, represented by the segment V820-P964. (2) It exists as a homo-dimer and contains seven conserved catalytic elements (CEs) wedged into seven conserved motifs. (3) It also contains a conserved 21-residue neurocalcin δ-modulated structural domain, V836-L857. (4) Site-directed mutagenesis documents that each of the seven CEs governs the cyclase’s catalytic activity. (5) In contrast to the soluble and the bacterium MGC which use Mn2+-GTP substrate for catalysis, MGC CCD uses the natural Mg2+-GTP substrate. (6) Strikingly, the MGC CCD requires anchoring by the Transmembrane Domain (TMD) to exhibit its major (∼92%) catalytic activity; in isolated form the activity is only marginal. This feature is not linked with any unique sequence of the TMD; there is minimal conservation in TMD. Finally, (7) the seven CEs control each of four phototransduction pathways- -two Ca2+-sensor GCAPs-, one Ca2+-sensor, S100B-, and one bicarbonate-modulated. The findings disclose that the CCD of ROS-GC1 has built-in regulatory elements that control its signal translational activity. Due to conservation of these regulatory elements, it is proposed that these elements also control the physiological activity of other members of MGC family.

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Section: Resultsmentioning

confidence: 99%

Membrane Guanylate Cyclase catalytic Subdomain: Structure and Linkage with Calcium Sensors and Bicarbonate

Ravichandran

Duda

Pertzev

et al. 2017

Front. Mol. Neurosci.

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“…Low levels of cGMP due to enhanced expression of PDE5, a cGMP specific phosphodiesterase characterize some cancer cells (14). Increasing cGMP levels by inhibiting PDE5 blocks MDA-231 and ZR75-1 breast cancer cell growth but not growth of non-transformed human mammary epithelial cells that do not express PDE5 (14, 34).…”

Section: Discussionmentioning

confidence: 99%

“…Increasing cGMP levels by inhibiting PDE5 blocks MDA-231 and ZR75-1 breast cancer cell growth but not growth of non-transformed human mammary epithelial cells that do not express PDE5 (14, 34). While not all downstream targets of cGMP/PKG are known, inhibition of PDE5 is associated with down-regulation of β-catenin expression and downstream TCF-4 promoter activity in these breast cancer cell lines (14, 34). Our findings demonstrate that increased cellular cGMP levels and PKG activity, reduced β-catenin expression and TCF-4 promoter activity, and enhanced tumor cell killing are also obtained by modulating BH4:BH2 with a natural endogenous molecule.…”

Section: Discussionmentioning

confidence: 99%

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The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression

Rabender

Alam

Sundaresan

et al. 2015

Molecular Cancer Research

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Here evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast to normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on HPLC analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin: dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid and head and neck tumors compared to normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling including increased cGMP-dependent protein kinase (PKG) activity, decreased β-catenin expression and TCF4 promoter activity, and reduced NF-κB promoter activity. Sepiapterin inhibited breast tumor cell growth in vitro and in vivo as measured by clonogenic assay, Ki67 staining and 18F-deoxyglucose positron emission tomography (FDG-PET). In summary, using diverse tumor types, it is demonstrated that the BH4:BH2 ratio is lower in tumor tissues and as a consequence nitric oxide synthase activity generates more peroxynitrite and superoxide anion than nitric oxide resulting in important tumor growth promoting and anti-apoptotic signaling properties. Implications The synthetic BH4, Kuvan®, is used to elevate BH4:BH2 in some phenylketonuria patients and to treat diseases associated with endothelial dysfunction suggesting a novel, testable approach for correcting an abnormality of tumor metabolism to control tumor growth.

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“…Discussion of oncogenic signaling associated with the other modes of NO signaling can be found elsewhere. [32][33][34] At least 1000 proteins modified by S-nitrosylation have been identified in mammalian cells.[35] Physiological nitrosylation of signaling proteins is directly related to the proliferation of normal and cancer cells. [28][29][30] Cancer is a major worldwide health problem, displaying high incidence rates in developed as well as developing countries.…”

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confidence: 99%

Nitric oxide: Protein tyrosine phosphorylation and protein S-nitrosylation in cancer

et al. 2015

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N itric oxide (NO) is a free radical with signaling capacity that plays an important role in the cardiovascular, neuronal, and immune systems, among others. NO regulates a number of physiological processes through the activation of two major signaling pathways: The activation of the enzyme guanylyl cyclase to form cGMP and S-nitrosylation, a covalent attachment of an NO moiety to a reactive cysteine residue in peptides and proteins. NO produced by the endothelial isoform of NO synthase (eNOS) regulates blood pressure. NO produced in neurons by the neuronal NOS isoform (nNOS) functions as a neurotransmitter. The constitutively expressed isoforms eNOS and nNOS release low fluxes of NO that are associated with cell protection and proliferation. Inflammatory cytokines and toxins induce the inducible NOS isoform (iNOS) in macrophages. Production of NO under these conditions is much higher compared to its production by constitutive enzymes. [1] Higher NO fluxes such as those produced by iNOS stimulated by inflammatory cytokines in macrophages or generated by millimolar concentrations of NO donors are cytotoxic and promote apoptosis. [2] The constitutive NOS isoforms have been detected in some malignant tumors. Activation of eNOS is involved in the initiation and maintenance of tumor growth in pancreatic cancer cell lines.[3] Tumor progression in prostate cancer is associated with eNOS expression, while malignant melanoma progression is associated with nNOS expression. [4,5] The iNOS isoform is ubiquitously distributed in malignant tumors, but its role in tumor development is highly complex and poorly understood.[6] The expression levels of iNOS and Special EditionCancer is a worldwide health problem leading to a high incidence of morbidity and mortality. Malignant transformation can occur by expression of oncogenes, over-expression and deregulated activation of proto-oncogenes, and inactivation of tumor suppressor genes. These cellular actions occur through stimulation of oncogenic signaling pathways. Nitric oxide (NO) can induce genetic changes in cells and its intracellular generation can lead to tumor formation and progression. It can also promote anti-tumor activities. The pro-and anti-tumor activities of NO are dependent on its intracellular concentration, cell compartmentalization, and cell sensitivity. NO affects a number of oncogenic signaling pathways. This review focuses on two oncogenic signaling pathways: NO-EGFR-Src-FAK and NO-Ras-EGFR-ERK1/2 MAP kinases. In these pathways, low to intermediate concentrations of NO/S-nitrosothiols (RSNOs) stimulate oncogenic signaling, while high concentrations of NO/RSNO stimulate anti-oncogenic signaling. Increasing knowledge on pro-and anti-tumorigenic activities of NO and related reactive species such as RSNOs has fostered the research and synthesis of novel NO-based chemotherapeutic agents. RSNOs, effective as NO donors and trans-nitrosylating agents under appropriate conditions, may operate as potential chemotherapeutic agents. (Biomed J 2015;38:380-388) associat...

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cGMP signaling as a target for the prevention and treatment of breast cancer

Cited by 28 publications

References 49 publications

Membrane Guanylate Cyclase catalytic Subdomain: Structure and Linkage with Calcium Sensors and Bicarbonate

Membrane Guanylate Cyclase catalytic Subdomain: Structure and Linkage with Calcium Sensors and Bicarbonate

The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression

Nitric oxide: Protein tyrosine phosphorylation and protein S-nitrosylation in cancer

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