Guanylyl Cyclase-cGMP Signaling Pathway in Melanocytes: Differential Effects of Altered Gravity in Non-Metastatic and Metastatic Cells.

Krassimira Ivanova,Ruth Hemmersbach

doi:10.3390/ijms21031139

Krassimira Ivanova, Ruth Hemmersbach

Open Access

https://doi.org/10.3390/ijms21031139

Copy DOI

Abstract

Human epidermal melanocytes as melanin producing skin cells represent a crucial barrier against UV-radiation and oxidative stress. It was shown that the intracellular signaling molecule cyclic guanosine-3′,5′-monophosphate (cGMP), generated by the guanylyl cyclases (GCs), e.g., the nitric oxide (NO)-sensitive soluble GC (sGC) and the natriuretic peptide-activated particulate GC (GC-A/GC-B), plays a role in the melanocyte response to environmental stress. Importantly, cGMP is involved in NO-induced perturbation of melanocyte–extracellular matrix interactions and in addition, increased NO production during inflammation may lead to loss of melanocytes and support melanoma metastasis. Further, the NO-sensitive sGC is expressed predominantly in human melanocytes and non-metastatic melanoma cells, whereas absence of functional sGC but up-regulated expression of GC-A/GC-B and inducible NO synthase (iNOS) are detected in metastatic cells. Thus, suppression of sGC expression as well as up-regulated expression of GC-A/GC-B/iNOS appears to correlate with tumor aggressiveness. As the cGMP pathway plays important roles in melanocyte (patho)physiology, we present an overview on the differential effects of altered gravity (hypergravity/simulated microgravity) on the cGMP signaling pathway in melanocytes and melanoma cells with different metastatic potential. We believe that future experiments in real microgravity may benefit from considering cGMP signaling as a possible factor for melanocyte transformation and in medication.

Highlights

Cyclic guanosine-3,5 -monophosphate is an important intracellular signaling molecule that regulates severalphysiological processes in multiple cell types
We further showed that hypergravity was able to induce an increase in the mRNA expression of endothelial isoform (eNOS), soluble GC (sGC)-β1 subunit, and multidrug resistance proteins 4 (MRP4)/MRP5 in non-metastatic 1F6 melanoma cells, but there were no apparent changes in the mRNA expression of guanylyl cyclases (GCs)-A/GC-B and inducible NO synthase (iNOS) compared to 1 g controls [82]
Concerning the molecular player of the particulate GCs (pGCs)-cGMP signaling in highly metastatic melanoma cells, we reported a strong reduction in the expression of both GC-A and GC-B under simulated microgravity conditions in comparison to 1 g controls [82]

Summary

Introduction

Cyclic guanosine-3 ,5 -monophosphate (cGMP or cyclic GMP) is an important intracellular signaling molecule that regulates several (patho)physiological processes in multiple cell types. The effective intracellular accumulation of GMP is dependent on the activities of the GCs and the metabolic degradation by the PDEs, and on the active export into the extracellular space, e.g., via the multidrug resistance proteins 4 (MRP4) and 5 (MRP5) as selective cGMP exporters [43]. Both MRP4 and MRP5 export nucleoside analogs that are used in antiviral and anticancer therapy [44]

Guanylyl Cyclase-cGMP Signaling Pathway in Melanocytes

Guanylyl Cyclase-cGMP Signaling Pathway in Melanoma

Experimental Approaches to Alter the Influence of Gravity on the Ground

Effects of Altered Gravity in Metastatic Melanoma Cells

Findings

Conclusion and Perspectives