The cyclic GMP/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma

Tuttle, Traci R.; Mierzwa, Michelle; Wells, Susanne I.; Fox, Sejal R.; Ben‐Jonathan, Nira

doi:10.1016/j.canlet.2015.10.024

Cited by 52 publications

(51 citation statements)

References 41 publications

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“…It has been reported that cGMP promoted tumorigenesis and anticancer effects. For example, the activated cGMP/PKG pathway induced multiple cancers (33,(35)(36)(37). Studies found specifically activated protein kinase G1 (PKG1) triggered MAPK signaling pathway to promote growth of melanoma (38).…”

Section: Discussionmentioning

confidence: 99%

Quantitative Analysis of Proteome in Non-functional Pituitary Adenomas: Clinical Relevance and Potential Benefits for the Patients

Cheng

Wang

et al. 2019

Front. Endocrinol.

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Background: Non-functional pituitary adenoma (NFPA) is a common tumor that occurs in the pituitary gland, and generally without any symptoms at its early stage and without clinical elevation of hormones, which is commonly diagnosed when it grows up to compress its surrounding tissues and organs. Currently, the pathogenesis of NFPA has not been clarified yet. It is necessary to investigate molecular alterations in NFPA, and identify reliable biomarkers and drug therapeutic targets for effective treatments.Methods: Tandem mass tags (TMT)-based quantitative proteomics was used to identify and quantify proteins in NFPAs. GO and KEGG enrichment analyses were used to analyze the identified proteins. Differentially expressed genes (DEGs) between NFPA and control tissues were obtained from GEO datasets. These two sets of protein and gene data were analyzed to obtain overlapped molecules (genes; proteins), followed by further GO and KEGG pathway analyses of these overlapped molecules, and molecular network analysis to obtain the hub molecules with Cytoscape. Two hub molecules (SRC and AKT1) were verified with Western blotting.Results: Totally 6076 proteins in NFPA tissues were identified, and 3598 DEGs between NFPA and control tissues were identified from GEO database. Overlapping analysis of 6076 proteins and 3598 DEGs obtained 1088 overlapped molecules (DEGs; proteins). KEGG pathway analysis of 6076 proteins obtained 114 statistically significant pathways, including endocytosis, and spliceosome signaling pathways. KEGG pathway analysis of 1088 overlapped molecules obtained 52 statistically significant pathways, including focal adhesion, cGMP-PKG pathway, and platelet activation signaling pathways. These pathways play important roles in cell energy supply, adhesion, and maintenance of the tumor microenvironment. According to the association degree in Cytoscape, ten hub molecules (DEGs; proteins) were identified, including GAPDH, ALB, ACACA, SRC, ENO2, CALM1, POTEE, HSPA8, DECR1, and AKT1. Western-blotting analysis confirmed the upregulated expressions of SRC and PTMScan experiment confirmed the increased levels of pAKT1, in NFPAs compared to controls.Cheng et al. Non-functional Pituitary Adenoma Proteomic ProfilingConclusions: This study established the large-scale quantitative protein profiling of NFPA tissue proteome. It offers a basis for subsequent in-depth proteomics analysis of NFPAs, and insight into the molecular mechanism of NFPAs. It also provided the basic data to discover reliable biomarkers and therapeutic targets for NFPA patients.

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Section: Discussionmentioning

confidence: 99%

Quantitative Analysis of Proteome in Non-functional Pituitary Adenomas: Clinical Relevance and Potential Benefits for the Patients

Cheng

Wang

et al. 2019

Front. Endocrinol.

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“…We have previously shown that BAY reduced the viability of HNSCC cells primarily by inducing apoptosis, while only slightly reducing cell proliferation [22]. Here we examined whether YC-1 or BAY enhanced the apoptotic effects of cisplatin in HNSCC cells.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, PKG-Iα has been reported to have pro-tumorigenic effects [35, 36], while PKG-Iβ [37, 38] and PKG-II [13] had antineoplastic effects. Our previous studies have shown that all four HNSCC cell lines examined express PKGIβ and PKGII, but had no detectable levels of PKGIα transcripts [22]. …”

Section: Discussionmentioning

confidence: 99%

“…For example, Riociguat, a NO-independent sGC stimulator, is used to treat pulmonary hypertension [19], while selective PDE5 inhibitors such as Tadalafil (Cialis) and Sildenafil (Viagra) are used to treat erectile dysfunction [20]. Thomson et al [21] were the first to link the cGMP/PKG pathway to inhibition of growth of colon cancer cells by a mechanism involving the suppression of β-catenin.We recently reported that activation of the cGMP pathway in HNSCC cells by sGC activators or PDE5 inhibitors reduced cell viability and clonogenic growth and induced apoptosis [22]. Others found that YC-1, a sGC activator, as well as PDE5 inhibitors, enhance the efficacy of a variety of chemotherapeutic agents [23-25].…”

Section: Introductionmentioning

confidence: 99%

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Soluble guanylate cyclase stimulators increase sensitivity to cisplatin in head and neck squamous cell carcinoma cells

et al. 2017

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Head and neck squamous cell carcinoma (HNSCC) is an aggressive and often fatal disease. Cisplatin is the most common chemotherapeutic drug in the treatment of HNSCC, but intrinsic and acquired resistance are frequent, and severe side effects occur at high doses. The second messenger cyclic GMP (cGMP) is produced by soluble guanylate cyclase (sGC). We previously reported that activation of the cGMP signaling cascade caused apoptosis in HNSCC cells, while others found that this pathway enhances cisplatin efficacy in some cell types. Here we found that sGC stimulators reduced HNSCC cell viability synergistically with cisplatin, and enhanced apoptosis by cisplatin. Moreover, the sGC stimulators effectively reduced viability in cells with acquired cisplatin resistance, and were synergistic with cisplatin. The sGC stimulator BAY 41-2272 reduced expression of the survival proteins EGFR and β-catenin, and increased pro-apoptotic Bax, suggesting a potential mechanism for the anti-tumorigenic effects of these drugs. The sGC stimulator Riociguat is FDA-approved to treat pulmonary hypertension, and others are being studied for therapeutic use in several diseases. These drugs could provide valuable addition or alternative to cisplatin in the treatment of HNSCC.

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“…cGMP can activate cGMP-dependent protein kinase (PKG) and PDE enzymes. It also causes ion fluxes and protein phosphorylation that can affect genes expression or other cellular responses [6,11,12] . Recently, the overexpression of PDE5 has been reported in several human carcinomas, including breast cancer, and suggested that PDE5 expression has positive correlation with tumor grade, lymph node involvement, and invasive potential, as well as decreasing survival rate in patients.…”

Section: Introductionmentioning

confidence: 99%

Hydroalcoholic Extract of Levisticum officinale Increases cGMP Signaling Pathway by Down-Regulating PDE5 Expression and Induction of Apoptosis in MCF-7 and MDA-MB-468 Breast Cancer Cell Lines

Sargazi

Saravani

Shahraki

2019

ibj

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Background: This study aimed to investigate Levisticum officinale hydroalcoholic extract (LOHE) effect on both cGMP signaling pathway and phosphodiesterase 5 (PDE5) gene expression pattern and to examine the role of LOHE in apoptosis induction of MCF-7 and MDA-MB-468 cell lines. Methods: The half maximal inhibitory concentration (IC50) of LOHE was examined in both cell lines using the MTT assay. Using IC50 values of LOHE on both cells, the type of cell death was detected by flowcytometric analysis. The values of PDE5 and cGMP were evaluated by real-time PCR and ELISA methods, respectively. Results: The IC50 values were measured as 150 μg/ml for MDA-MB-468 and 200 μg/ml for MCF-7. At 12 hour of treatment, a significant decrease in the PDE5 expression and maximum increase in the amount of intracellular cGMP were observed (p < 0.05). However, these effects were more noticeable in MDA-MB-468 triple-negative cells. Conclusion: Our data suggest that LOHE extract could be a potential source for new strategies towards targeting both PDE5 and cGMP signaling pathways.

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The cyclic GMP/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma

Cited by 52 publications

References 41 publications

Quantitative Analysis of Proteome in Non-functional Pituitary Adenomas: Clinical Relevance and Potential Benefits for the Patients

Quantitative Analysis of Proteome in Non-functional Pituitary Adenomas: Clinical Relevance and Potential Benefits for the Patients

Soluble guanylate cyclase stimulators increase sensitivity to cisplatin in head and neck squamous cell carcinoma cells

Hydroalcoholic Extract of Levisticum officinale Increases cGMP Signaling Pathway by Down-Regulating PDE5 Expression and Induction of Apoptosis in MCF-7 and MDA-MB-468 Breast Cancer Cell Lines

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