Cyclic GMP-dependent protein kinase II inhibits cell proliferation, Sox9 expression and Akt phosphorylation in human glioma cell lines

Swartling, Fredrik J.; Ferletta, Maria; Kastemar, Marianne; Weiss, William A.; Westermark, Bengt

doi:10.1038/onc.2009.168

Cited by 80 publications

(72 citation statements)

References 40 publications

(47 reference statements)

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“…Increasing evidence indicates that this enzyme may be important in the activity of cancer cells; this may include inhibiting migration and proliferation in certain cancer cell types (5,7,8). Our previous results demonstrated that PKG II may inhibit LPA-induced migration by decreasing RhoA activation (13).…”

Section: Discussionmentioning

confidence: 99%

“…Although classically recognized for its ability to modulate intestinal secretion, bone growth and nervous system functions (2-4), PKG II has also been reported to act as an inhibitory component of signal transduction processes in certain cancer cell types. 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.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…They also found that activation of PKGII could induce apoptosis of human prostate cells. 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.…”

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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“…The Akt signalling pathway is often activated in gliomas and the PDGFR is frequently constitutively activated (Nister, et al, 1988;Phillips, et al, 2006). Further, reduced expression of Sox9 by siRNA is decreasing the cell proliferation rate in glioma cells (Swartling, et al, 2009). In addition to gliomas, Sox9 is expressed in prostate cancers and Sox9 suppression in prostate cancer cause a downregulation of cell growth (Wang, et al, 2007) which support our findings in glioma.…”

Section: The Function Of Sox9 In Glioma and Medulloblastomamentioning

confidence: 99%

“…The reported expression data on Sox9 match nicely the expression data from the IST database as well as the data from the HPA database (Table 2). Moreover, we have investigated the effect of overexpressing cGKII (cyclic guanosine monophosphate (cGMP)-dependent protein kinase II) which results in reduced expression of Sox9 and PDGFR and this is followed by dephosphorylation of Akt, suggesting a connection between Sox9, PDGFR and the Akt signalling pathway in glioma (Swartling, et al, 2009). The Akt signalling pathway is often activated in gliomas and the PDGFR is frequently constitutively activated (Nister, et al, 1988;Phillips, et al, 2006).…”

Section: The Function Of Sox9 In Glioma and Medulloblastomamentioning

confidence: 99%

The Role of Sox Transcription Factors in Brain Tumourigenesis

Ferletta¹

2011

Molecular Targets of CNS Tumors

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Cyclic GMP-dependent protein kinase II inhibits cell proliferation, Sox9 expression and Akt phosphorylation in human glioma cell lines

Cited by 80 publications

References 40 publications

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

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

The Role of Sox Transcription Factors in Brain Tumourigenesis

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