Abstract
Ectopic expression of a neuronal receptor, Metabotropic Glutamate Receptor 1 (
Grm1
), in melanocytes has been implicated in melanoma development in mouse models. The human relevance of this receptor’s involvement in melanoma pathogenesis was demonstrated by detecting GRM1 expression in subsets of human melanomas, an observation lacking in benign nevi or normal melanocytes.
Grm1
-transformed mouse melanocytes and a conditional
Grm1
transgenic mouse model confirmed a requirement for sustained expression of Grm1 for the maintenance of transformed phenotypes
in vitro
and tumorigenicity
in vivo
. Here, we investigate if continued GRM1 expression is also required in human melanoma cell lines by using two inducible, silencing RNA systems: the ecdysone/Ponasterone A and tetracycline on/off approaches to regulate GRM1 expression in the presence of each inducer. Various
in vitro
assays were performed to assess consequences of a reduction in GRM1 expression on cell proliferation, apoptosis, downstream targeted signaling pathways and
in vivo
tumorigenesis. We demonstrated that suppression of GRM1 expression in several human melanoma cell lines resulted in a reduction in the number of viable cells and a decrease in stimulated MAPK and PI3K/AKT and suppressed tumor progression
in vivo
. These results reinforce earlier observations where a reduction in cell growth
in vitro
and tumorigenesis
in vivo
were correlated with decreased GRM1 activities by pharmacological inhibitors of the receptor, supporting the notion that GRM1 plays a role in the maintenance of transformed phenotypes in human melanoma cells
in vitro
and
in vivo
and potentially be a therapeutic target for the treatment of melanoma.