Hypergravitationsinduzierte Effekte auf cGMP-Konzentration humaner Melanozyten und Melanomzellen

Environmental signals such as an altered acceleration vector (micro- and hypergravity) may influence cell morphology, proliferation, response to growth factors, gene expression, and metabolism. Despite the growing interest in the regulation of signaling activities in normal and transformed cells under altered gravity conditions, little is known how normal human melanocytes and melanoma cells respond to such environmental factors. In human skin, melanocytes function as a pivotal protective barrier against UV irradiation and oxidative stress by generating the radical-scavenging pigment melanin. Moreover, as human skin is repeatedly exposed to mechanical stimuli, it has been found that human melanocytes may also sense mechanical forces such as mechanical pressure and cyclic stretch. As guanosine 3',5'-cyclic monophosphate (cGMP) is known to play an important signaling role in human melanocytes and different guanylyl cyclase isoforms are responsible for the cGMP synthesis in nonmetastatic and metastatic melanoma cells, the effects of hypergravity on the regulation of cGMP levels in normal human melanocytes and in melanoma cell lines with different metastatic potential have been investigated. Hypergravity stimulus was provided using horizontal centrifugal acceleration. The present study demonstrates that long-term exposure of cultured human melanocytes and nonmetastatic melanoma cells to hypergravity (up to 5g for 24 h) induced a decrease in intracellular and an increase in extracellular cGMP levels in the presence of isobutylmethylxanthine as a nonspecific inhibitor of the phosphodiesterase-mediated cyclic nucleotide hydrolysis. Such alterations were equally prominent despite the presence of trequinsin and zaprinast as inhibitors of cGMP-specific phosphodiesterases and of the cGMP transport by the multidrug resistance proteins MRP4 and MRP5. Importantly, expression and stimulation of soluble guanylyl cyclase isoform by a nitric oxide donor and of the membrane isoforms by natriuretic peptides were not changed by hypergravity in comparison to 1g controls. Thus, the hypergravity-induced alteration in cGMP levels was due to a stimulation of the cGMP export into the extracellular space. On the other hand, cyclic AMP efflux in normal human melanocytes and nonmetastatic melanoma cells was not altered, but production of cAMP appeared to be stimulated by centrifugal acceleration as is evident by the similar increase in intra- and extracellular cAMP levels, which was associated with enhanced melanin formation in pigmented human melanocytes. In contrast, metastatic melanoma cells were apparently insensitive to hypergravity. Taken together, the present results indicate that the environment created by centrifugal acceleration represents a new factor for regulating cyclic nucleotide levels in human melanocytes.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2003

Author dc:creator

• Hamidi Zadeh, Nahid

Contributors dc:contributor

• Gerzer, Rupert

• info:eu-repo/classification/ddc/610
• Medizin

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-123568%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:61964