Cyclic GMP induced apoptosis via protein kinase G in oestrogen receptor‐positive and ‐negative breast cancer cell lines

Fallahian, Faranak; Karami-Tehrani, Fatemeh; Salami, Siamak; Aghaei, Mahmoud

doi:10.1111/j.1742-4658.2011.08260.x

Cited by 107 publications

(110 citation statements)

References 30 publications

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“…In addition, dysregulation of cGMP homeostasis was observed in various (patho)physiologic conditions, including cancers. Indeed, cGMP signaling, through activation of downstream effectors (i.e., cGMP-dependent protein kinase G-PKG, cyclic-nucleotide-gated ion channels) and/or crosstalk with cAMP pathways, appears to play an important role in promoting apoptosis and inhibiting proliferation of certain epithelial cells (6,7). Interestingly, PKG expression or cGMP levels are reduced in cancer cells and tissues compared with their normal counterparts (8,9).…”

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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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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“…Swartling et al (5) found that this kinase was involved in regulating cell proliferation in glioma cells. Fallahian et al (6) evaluated the significance of the downregulation of PKG II expression in breast cancer and found that PKGII expression was downregulated in the breast tumors compared to those of normal tissue counterparts, which is an important evidence to support the antitumor activity of this kinase. Previous results from our laboratory demonstrated that PKG II inhibited the proliferation and migration of gastric cancer cell lines through the suppression of epidermal growth factor (EGF)-induced activation of the EGF receptor and related signal transduction pathways (7,8).…”

Section: Introductionmentioning

confidence: 99%

Type II cyclic guanosine monophosphate-dependent protein kinase inhibits Rac1 activation in gastric cancer cells

Wang

Chen

et al. 2015

Oncology Letters

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Abstract. Enhanced motility of cancer cells is a critical step in promoting tumor metastasis, which remains the major cause of gastric cancer-associated mortality. The small GTPase Rac1 is a key signaling component in the regulation of cell migration. Previous studies have demonstrated that Rac1 activity may be regulated by protein kinase G (PKG); however, the underlying mechanism is not yet clear. The current study aimed to investigate the effect of type II cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG II) on Rac1 activity. The human gastric cancer cell line AGS was infected with adenoviral constructs encoding PKG II to increase the expression of this enzyme, and treated with a cGMP analog (8-pCPT-cGMP) to induce its activation. A Transwell assay was employed to measure cell migration, and the activity of Rac1 was assessed using a pull-down assay. Immunoprecipitation was used to isolate the Rac1 protein. Phosphorylation of phosphatidylinositol 4,5 bisphosphate 3 kinase (PI3K) and its downstream effecter protein kinase B (Akt) are associated with lysophosphatidic acid (LPA)-induced motility/migration of cancer cells. Extracellular signal regulated kinase (ERK) is the major signaling molecule of the Mitogen activated protein kinase (MAPK) mediated signaling pathway. ERK and its upstream activator MAPK kinase (MEK) are also involved in LPA-induced motility/migration of cancer cells. Phosphorylation of PI3K/Akt, MEK/ERK and enriched Rac1 were detected by western blotting. The results revealed that blocking the activation of Rac1 by ectopically expressing an inactive Rac1 mutant (T17N) impeded LPA-induced cell migration. Increased PKG II activity inhibited LPA-induced migration and LPA-induced activation of Rac1; however, it had no effect on the phosphorylation of Rac1. PKG II also inhibited the activation of PI3K/Akt and MEK/ERK mediated signaling, which is important for LPA-induced Rac1 activation. These results suggest that PKG II affects LPA-stimulated migration of AGS cells by blocking Rac1 activation, via inhibition of PI3K/Akt and MEK/ERK mediated signaling.

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“…In 2009, Swartling et al (22) reported that PKGII inhibited the proliferation of human neuroglioma cells and the inhibition was related to the decrease of the expression of transcription factor Sox9 and the phosphorylation of Akt. In 2011, Fallahian et al (23) reported that cGMP could induce apoptosis of breast cancer cells and this effect was related to PKGII. In our laboratory, the proliferation inhibitory effect of PKGII has been confirmed by several methods including MTT assay, 3 H-labeled thymidine uptake assay, anchorageindependent growth assay, and tumor formation in nude mouse (13).…”

Section: Discussionmentioning

confidence: 99%

Type II cGMP-dependent protein kinase inhibits EGF-induced MAPK/JNK signal transduction in breast cancer cells

et al. 2012

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Abstract. Our previous research data showed that type II cGMPdependent protein kinase (PKGII) inhibited EGF-induced MAPK/ERK-mediated signal transduction through blocking the phosphorylation of EGFR caused by EGF. Since EGFR also mediates other MAPK-mediated signal transduction pathways, this study was designed to investigate whether PKGII inhibits EGF-induced MAPK/c-Jun N-terminal kinase (JNK) signal transduction. MCF-7 human breast cancer cells were infected with adenoviral constructs encoding the cDNA of PKGII (pAd-PKGII) to increase the expression of PKGII and treated with 8-pCPT-cGMP to activate the enzyme. Western blotting was applied to detect the phosphorylation/activation of EGFR, JNK, MKK7 and c-Jun. The Pull-down method was used to detect the activation of Ras protein. Co-IP was used to analyze the binding between Grb2 and Sos1. TUNEL staining was used to detect the apoptosis of MCF-7 cells. The results showed that EGF treatment increased the phosphorylation of EGFR, the binding between Grb2 and Sos1, the activation of Ras, and the phosphorylation/activation of MKK7, JNK and c-Jun, but decreased the apoptosis of the cells. Increase of PKGII activity through infection with pAd-PKGII and stimulation with 8-pCPT-cGMP efficiently reversed the above changes caused by EGF. The results suggest that PKGII also inhibits EGF-induced MAPK/JNK-mediated signal transduction and further confirmed that PKGII can block the activation of EGFR.

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Cyclic GMP induced apoptosis via protein kinase G in oestrogen receptor‐positive and ‐negative breast cancer cell lines

Cited by 107 publications

References 30 publications

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

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

Type II cyclic guanosine monophosphate-dependent protein kinase inhibits Rac1 activation in gastric cancer cells

Type II cGMP-dependent protein kinase inhibits EGF-induced MAPK/JNK signal transduction in breast cancer cells

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