AbstractMalignant pleural mesothelioma is a highly aggressive tumor arising from the mesothelial cells that line the pleural cavities. This tumor is resistant to most conventional anticancer treatments and appears to be very sensitive to growth-promoting influences of cytokines and growth factors. Identification of natural inhibitory pathways that control growth should aid discovery of novel therapeutic approaches. We hypothesized that α-melanocyte-stimulating hormone (α-MSH), which is produced by many cell types and antagonizes cytokines and growth factors, could be an endogenous inhibitory molecule in mesothelioma. Twelve mesothelioma cell lines were established from pleural effusions of patients with malignant mesothelioma. Mesothelioma cells were found to express mRNA for proopiomelanocortin and its processing enzymes; release α-MSH peptide into supernatants; and express melanocortin 1 receptor (MC1R), the high-affinity receptor for α-MSH. Immunoneutralization of MC1R in the cell lines enhanced expression of interleukin-8 (IL-8), IL-6, and transforming growth factor-β. These molecules promote mesothelioma proliferation and are considered therapeutic targets in this tumor. Coincubation of mesothelioma cells with synthetic α-MSH significantly reduced cell proliferation. The present research shows an autocrine-inhibitory circuit based on α-MSH and its receptor MC1R. Activation of MC1R by selective peptides or peptidomimetics might provide a novel strategy to reduce mesothelioma cell proliferation by taking advantage of this endogenous inhibitory circuit.