New dimeric cGMP analogues reduce proliferation in three colon cancer cell lines

Hoffmann, Dorit; Rentsch, Andreas; Vighi, Eleonora; Bertolotti, Evelina; Comitato, Antonella; Schwede, Frank; Genieser, Hans‐Gottfried; Marigo, Valeria

doi:10.1016/j.ejmech.2017.09.053

Cited by 11 publications

(11 citation statements)

References 30 publications

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“…Therefore, identification of PKG substrates and their downstream signaling pathways in photoreceptors might help to find generic, new targets for the treatment of IRDs. More insight on the effect of PKG modulators on PKGs will not only be beneficial in IRDs but also for cancer research, as PKG activators have been shown to reduce cell proliferation, activate cell death and limit cell invasion in different cancer cell models [11][12][13][14][15][16].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it has been shown in a CNG channel loss-of function mouse model that knocking out of prkg1 encoding for PKGI leads to sustained rod cell survival [10]. The correlation of PKG activation with cell death is corroborated by studies showing induction of apoptosis with PKG activation to stop tumor progression in colon cancers [11][12][13], breast cancers [14], ovarian cancers [15] and melanoma [16]. However, the signaling routes downstream of PKGI and PKGII that lead to cell death have not been identified yet.…”

Section: Introductionmentioning

confidence: 91%

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Identification of Novel Substrates for cGMP Dependent Protein Kinase (PKG) through Kinase Activity Profiling to Understand Its Putative Role in Inherited Retinal Degeneration

Roy

Groten

Marigo

et al. 2021

IJMS

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Inherited retinal degenerative diseases (IRDs), which ultimately lead to photoreceptor cell death, are characterized by high genetic heterogeneity. Many IRD-associated genetic defects affect 3′,5′-cyclic guanosine monophosphate (cGMP) levels. cGMP-dependent protein kinases (PKGI and PKGII) have emerged as novel targets, and their inhibition has shown functional protection in IRDs. The development of such novel neuroprotective compounds warrants a better understanding of the pathways downstream of PKGs that lead to photoreceptor degeneration. Here, we used human recombinant PKGs in combination with PKG activity modulators (cGMP, 3′,5′-cyclic adenosine monophosphate (cAMP), PKG activator, and PKG inhibitors) on a multiplex peptide microarray to identify substrates for PKGI and PKGII. In addition, we applied this technology in combination with PKG modulators to monitor kinase activity in a complex cell system, i.e. the retinal cell line 661W, which is used as a model system for IRDs. The high-throughput method allowed quick identification of bona fide substrates for PKGI and PKGII. The response to PKG modulators helped us to identify, in addition to ten known substrates, about 50 novel substrates for PKGI and/or PKGII which are either specific for one enzyme or common to both. Interestingly, both PKGs are able to phosphorylate the regulatory subunit of PKA, whereas only PKGII can phosphorylate the catalytic subunit of PKA. In 661W cells, the results suggest that PKG activators cause minor activation of PKG, but a prominent increase in the activity of cAMP-dependent protein kinase (PKA). However, the literature suggests an important role for PKG in IRDs. This conflicting information could be reconciled by cross-talk between PKG and PKA in the retinal cells. This must be explored further to elucidate the role of PKGs in IRDs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Identification of Novel Substrates for cGMP Dependent Protein Kinase (PKG) through Kinase Activity Profiling to Understand Its Putative Role in Inherited Retinal Degeneration

Roy

Groten

Marigo

et al. 2021

IJMS

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“…Over the last ~40 years, the first generation of cGMP analogues have become standard tools for investigations of biochemical and physiological signal transduction pathways [60]. More recently, newly developed PKG activators have been shown to reduce proliferation in colon cancer cell lines [61], as well as in melanoma cells [62]. The use of PKG inhibitors contributed to identify a common non-apoptotic cGMP-dependent degeneration mechanism in different animal models for IRD [22].…”

Section: Targeting Cgmp-signalingmentioning

confidence: 99%

The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers

Tolone

Belhadj

Rentsch

et al. 2019

Genes

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Photoreceptor physiology and pathophysiology is intricately linked to guanosine-3’,5’-cyclic monophosphate (cGMP)-signaling. Here, we discuss the importance of cGMP-signaling for the pathogenesis of hereditary retinal degeneration. Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of different gene mutations. The cGMP-dependent cell death pathway may be targeted for the treatment of inherited photoreceptor degeneration, using specifically designed and formulated inhibitory cGMP analogues. Moreover, cGMP-signaling and its down-stream targets may be exploited for the development of novel biomarkers that could facilitate monitoring of disease progression and reveal the response to treatment in future clinical trials. We then briefly present the importance of appropriate formulations for delivery to the retina, both for drug and biomarker applications. Finally, the review touches on important aspects of future clinical translation, highlighting the need for interdisciplinary cooperation of researchers from a diverse range of fields.

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“…Smooth muscle cell proliferation contributes to excessive muscularization of pulmonary vessels during PH (2, 3). PKGI not only modulates vasotone and the pressure within arteries but also continues to emerge as an important player in cell differentiation, growth, proliferation, and cancer progression (72–74). RV hypertrophic remodeling and pressure were assessed in WT and KI mice subjected to hypoxia for 3 d, a time when pulmonary disulfide PKGIα was elevated (Figs.…”

Section: Resultsmentioning

confidence: 99%

Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension

Rudyk

Rowan

Prysyazhna

et al. 2019

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

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Chronic hypoxia causes pulmonary hypertension (PH), vascular remodeling, right ventricular (RV) hypertrophy, and cardiac failure. Protein kinase G Iα (PKGIα) is susceptible to oxidation, forming an interprotein disulfide homodimer associated with kinase targeting involved in vasodilation. Here we report increased disulfide PKGIα in pulmonary arteries from mice with hypoxic PH or lungs from patients with pulmonary arterial hypertension. This oxidation is likely caused by oxidants derived from NADPH oxidase-4, superoxide dismutase 3, and cystathionine γ-lyase, enzymes that were concomitantly increased in these samples. Indeed, products that may arise from these enzymes, including hydrogen peroxide, glutathione disulfide, and protein-bound persulfides, were increased in the plasma of hypoxic mice. Furthermore, low-molecular-weight hydropersulfides, which can serve as “superreductants” were attenuated in hypoxic tissues, consistent with systemic oxidative stress and the oxidation of PKGIα observed. Inhibiting cystathionine γ-lyase resulted in decreased hypoxia-induced disulfide PKGIα and more severe PH phenotype in wild-type mice, but not in Cys42Ser PKGIα knock-in (KI) mice that are resistant to oxidation. In addition, KI mice also developed potentiated PH during hypoxia alone. Thus, oxidation of PKGIα is an adaptive mechanism that limits PH, a concept further supported by polysulfide treatment abrogating hypoxia-induced RV hypertrophy in wild-type, but not in the KI, mice. Unbiased transcriptomic analysis of hypoxic lungs before structural remodeling identified up-regulation of endothelial-to-mesenchymal transition pathways in the KI compared with wild-type mice. Thus, disulfide PKGIα is an intrinsic adaptive mechanism that attenuates PH progression not only by promoting vasodilation but also by limiting maladaptive growth and fibrosis signaling.

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New dimeric cGMP analogues reduce proliferation in three colon cancer cell lines

Cited by 11 publications

References 30 publications

Identification of Novel Substrates for cGMP Dependent Protein Kinase (PKG) through Kinase Activity Profiling to Understand Its Putative Role in Inherited Retinal Degeneration

Identification of Novel Substrates for cGMP Dependent Protein Kinase (PKG) through Kinase Activity Profiling to Understand Its Putative Role in Inherited Retinal Degeneration

The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers

Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension

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