Sulindac Selectively Inhibits Colon Tumor Cell Growth by Activating the cGMP/PKG Pathway to Suppress Wnt/β-Catenin Signaling

Li, Nan; Xi, Yaguang; Tinsley, Heather N.; Gurpinar, Evrim; Gary, Bernard D.; Zhu, Bing; Li, Yonghe; Chen, Xi; Keeton, Adam B.; Abadi, Ashraf H.; Moyer, Mary Pat; Grizzle, William E.; Chang, Wen‐Chi L.; Clapper, Margie L.; Piazza, Gary A.

doi:10.1158/1535-7163.mct-13-0048

Cited by 109 publications

(103 citation statements)

References 37 publications

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“…Reduced β-catenin expression is observed with PKG overexpression in cultured colorectal tumor cells (13, 32) and in both colorectal and breast tumor cells by incubating with a cGMP phosphodiesterase inhibitor (33, 34). MCF-7 cells were treated with 20 µM SP with or without the PKG inhibitor, KT5823 (a specific PKG inhibitor, IC50 20nM), for up to 3 days.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression

Rabender

Alam

Sundaresan

et al. 2015

Molecular Cancer Research

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“…These agents are nonsteroidal anti-inflammatory drugs that have shown significant inhibition of cancer progression in different preclinical models and have been used in the treatment of colon cancer in human patients (24). The mechanism of action of these drugs is complex (31) and includes, among various targets, inhibition of proteasome-dependent degradation of β-catenin, downregulation of β-catenin transcription, and inhibition of β-catenin nuclear localization through inhibition of cGMP-PDE5 and activation of PKG (25,31). We report here a comparable activity of the two compounds in constraining CCM cavernomas in mice, but the sulfone metabolite is more promising for further pharmacological development because it is devoid of cyclooxygenase and platelet inhibitory activity (32,24).…”

Section: Discussionmentioning

confidence: 99%

Sulindac metabolites decrease cerebrovascular malformations in CCM3 -knockout mice

Bravi

Rudini

Cuttano

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

104

100

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Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of β-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin-driven transcription program that leads to endothelial-tomesenchymal transition. TGF-β/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate β-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.cerebral cavernous malformation | endothelial cells | β-catenin | sulindac metabolites | vascular pathology T he vascular malformations that characterize the disease known as cerebral cavernous malformation (CCM) are concentrated in the central nervous system, and they typically show multiple lumens and vascular leakage (1). These abnormalities can result in severe neurological symptoms, including hemorrhagic stroke (2), and, to date, the only possible therapy is surgery (3). In humans, loss-of-function mutations in any one of three independent genes known as cerebral cavernous malformation 1, 2, and 3 (CCM1, CCM2, and CCM3) are the cause of the genetic form of CCM (4). Similarly, in murine models, the vascular phenotype can be reproduced by endothelium-specific loss-of-function mutations of any one of these three CCM-linked genes (5-7).We have recently reported (7) that TGF-β/BMP signaling is activated after ablation of CCM1, CCM2, or CCM3 and induces endothelial-to-mesenchymal transition (EndMT) that plays a crucial role in the development of vascular malformations. Nevertheless, the sequence of signaling responses elicited by ablation of CCM genes still remains to be defined. Inhibitors of the TGF-β/BMP-signaling pathways reduce the number and size of the malformations, but not completely (7), suggesting that other signaling pathways may be implicated.The Wnt/β-catenin pathway, in synergy with TGF-β signaling (8), is responsible for the EndMT switch of endothelial cells giving rise to the heart cushion in the embryo. In addition, the knockdown of CCM1 and CCM3 expression in cultured aortic and artery endothelial cells promotes β-catenin signaling (9, 10), although no direct link with the in vivo model of the disease has been made. Activation of canonical Wnt/β-catenin signaling is critical for brain vascularization and acquisition, by the microvasculature, of blood-brain barr...

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“…Indeed, several in vitro observations have shown antiproliferative and proapoptotic effects of PDE5 inhibitors in cancer cell lines, as those of the breast (13,14,16,17). Another PDE5 inhibitor, the nonsteroidal anti-inflammatory drug exisulinid, inhibited growth and induced apoptosis in human tumor cells through cGMP elevation and PKG activation (12,18,19). PDE5 inhibitors also increased the efficacy of chemotherapy agents in cancer models (20).…”

Section: Introductionmentioning

confidence: 99%

Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy

Catalano

Campana

Giordano

et al. 2016

Clinical Cancer Research

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Purpose: By catalyzing cGMP hydrolysis, phosphodiesterase (PDE) 5 is a critical regulator of its concentration and effects in different (patho)physiologic processes, including cancers. As PDE5 is a known druggable target, we investigated the clinical significance of its expression in breast cancer and the underlying mechanisms by which it may contribute to tumor progression.Experimental Design: PDE5 expression was evaluated in seven breast cancer cell lines by RT-PCR and immunoblotting. To examine the impact of PDE5 on cancer phenotype, MCF-7 cells expressing lower levels of the enzyme were engineered to stably overexpress PDE5. Proliferation was evaluated by MTT assays, motility and invasion by wound-healing/transmigration/invasion assays, transcriptome-profiling by RNA-sequencing, and Rho GTPase signaling activation by GST-pulldown assays and immunoblotting. Clinical relevance was investigated by IHC on tissues and retrospective studies from METABRIC cohort.Results: PDE5 is differentially expressed in each molecular subtype of both breast cancer cell lines and tissues, with higher levels representing a startling feature of HER2-positive and triplenegative breast cancers. A positive correlation was established between elevated PDE5 levels and cancers of high histologic grade. Higher PDE5 expression correlated with shorter patient survival in retrospective analyses. On molecular level, stable PDE5 overexpression in Luminal-A-like MCF-7 cells resulted in enhanced motility and invasion through Rho GTPase signaling activation. Treatment of PDE5-stable clones with selective ROCK or PDE5 inhibitors completely restored the less motile and weak invasive behavior of control vector cells.Conclusions: PDE5 expression enhances breast cancer cell invasive potential, highlighting this enzyme as a novel prognostic candidate and an attractive target for future therapy in breast cancers.

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Sulindac Selectively Inhibits Colon Tumor Cell Growth by Activating the cGMP/PKG Pathway to Suppress Wnt/β-Catenin Signaling

Cited by 109 publications

References 37 publications

The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression

The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression

Sulindac metabolites decrease cerebrovascular malformations in CCM3 -knockout mice

Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy

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