Glutamate Signaling in Human Cancers

G-protein coupled receptors (GPCRs) represent a class of therapeutic targets that have been widely exploited for drug designs and development. Metabotropic glutamate receptors (mGluRs) belong to Class C GPCRs and are predominantly involved in maintaining cellular homeostasis in the central nervous system (CNS). The natural ligand of mGluRs, glutamate, interacts with recep‐ tor proteins leading to the activation of multiple signaling pathways. More recently, aberrant glutamate signaling has been shown to play a role in the transformation and maintenance of various cancer types, including melanoma. Glutamate secretion from these cells has been found to stimulate regulatory pathways that control tumor growth, proliferation and survival. In addition to synaptic transmissions, accumulating evidence suggesting other functional roles of glutamatergic signaling in human malignancies has presented intriguing possibilities to make mGluRs putative, novel targets for human cancer treatments. To this end, the aberrant expres‐ sion of metabotropic glutamate receptor 1 (mGluR1) was found as the driving force in inducing melanomagenesis in transgenic mouse models. Since then, other subtypes of mGluRs have been implicated in the pathogenesis of various cancer types such as malignant gliomas and medullo‐ blastomas. As such, increased efforts have been generated to elucidate the mechanisms by which mGluRs confer oncogenic potentials. This chapter summarizes our current knowledge on the participation of glutamate signaling in human cancers. Given that mGluRs are “druggable” members of the GPCR superfamily and their oncogenic implications in cancer, further under‐ standing on anti-mGluR signaling pathways will be beneficial.