Cholecystokinin Receptor Antagonist Suppresses Melanoma Growth by Inducing Apoptosis of Tumor Cells

Abstract

Melanoma is a malignant skin tumor with high metastatic activity. Although melanoma has been well-studied, its cellular kinetics remain elusive. The cholecystokinin (CCK) receptor is expressed in various types of tumors because CCK promotes the survival and proliferation of tumor cells. Thus, we hypothesized that the growth of melanoma was positively regulated by signals from the CCK receptor and sought to investigate whether CCK receptor antagonists affect the growth of melanoma cells expressing CCK receptor. Immunohistochemically, the CCK receptor A is expressed in the clinical specimens of melanoma. CCK receptor antagonists decreased the viability of melanoma cells by suppressing cell division and promoting apoptosis. CCK receptor antagonists also decreased the mitochondrial membrane potential through enhanced gene expression of the proapoptotic protein, Bcl2-associated X, and tumor suppressor, p53, suggesting that the antagonist induced the apoptosis of melanoma cells in a mitochondria-dependent manner. In addition, a caspase 3 inhibitor, Z-DEVD-FMK, partially blocked the antiviability of the antagonist, indicating that caspase 3 is involved in antagonist-induced apoptosis. Notably, tumor growth was attenuated when a CCK receptor antagonist was locally administered to the melanoma-bearing mice. Therefore, our study suggests the therapeutic potential of CCK receptor antagonists in the treatment of skin cancer.