Pharmacogenomics of metabotropic glutamate receptor subtype 1 and in vivo malignant melanoma formation

We have previously shown that ectopic expression of metabotropic glutamate receptor subtype 1 in melanocytes is essential for both development and in vivo growth of melanoma using newly developed transgenic mice which conditionally express metabotropic glutamate receptor subtype 1 (mGluR1). In this study, we developed conditional transgenic mice, which harbor melanocytes not only in the dermis and hair follicles but also in the epidermis using stem cell factor transgenic mice. Pigmented plaques on the backs, tails, ears or groins of the transgenic mice began to appear 13 weeks after activation of the mGluR1 transgene, and the transgenic mice produced melanomas at a frequency of 100% 36 weeks after transgene activation. Although this transgenic mouse harbors melanocytes in the epidermis, proliferation of melanoma cells took place in the dermis. To elucidate the signals involved in development and growth of melanoma, inhibitors to phospholipase C, protein kinase C and mitogen-activated protein kinase kinase 1/2, and antagonists to Ca2+ and calmodulin were administrated to transgenic mice. Each signal inhibitor to phospholipase, protein kinase C, Ca2+ release, calmodulin and mitogen-activated protein kinase kinase 1/2 inhibited melanoma development. However, once melanoma was developed, the growth of melanoma was dramatically inhibited only by the inhibitor to mitogen-activated protein kinase kinase 1/2 with partial inhibition by inhibitors to protein kinase C and phospholipase C. This inhibition of melanoma growth was well correlated with the expression of phosphorylated extracellular signal-regulated kinase 1/2 and Ki-67. These results indicate that for development of melanoma, activation of every signaling pathway from mGluR1 is required. However, for growth of melanoma, the extracellular signal-regulated kinase pathway plays a key role.