Human colorectal cancers express a constitutively active cholecystokinin-B/gastrin receptor that stimulates cell growth

Although ectopic expression of the cholecystokinin B/gastrin receptor (CCK-BR) is widely reported in human colorectal cancers, its role in mediating the proliferative effects of gastrin1-17 (G-17) on these cancers is unknown. Here we report the isolation of a novel splice variant of CCK-BR that exhibits constitutive (ligand-independent) activation of pathways regulating intracellular free Ca²⁺ ([Ca²⁺](i)) and cell growth. The splice variant (designated CCK-BRi4sv for intron 4-containing splice variant) is expressed in colorectal cancers but not in normal colonic mucosa adjacent to the cancer. Balb3T3 cells expressing CCK-BRi4sv exhibited spontaneous, ligand-independent, oscillatory increases in [Ca²⁺](i), whereas cells expressing wild-type CCK-BR did not. Primary cultures of cells isolated from resected colorectal cancers also exhibited a similar pattern of spontaneous [Ca²⁺](i) oscillations. For both Balb3T3 and primary tumor cells, application of G-17 (10 and 200 nM, respectively) caused an increase in [Ca²⁺](i). Selective CCK-BR antagonists blocked the G-17-stimulated Ca²⁺ responses but not the spontaneous [Ca²⁺](i) oscillations. Cells expressing CCK-BRi4sv exhibited an increased growth rate (~2.5-fold), in the absence of G-17, compared with cells expressing wild-type CCK-BR. The selective pattern of expression, constitutive activity, and trophic action associated with CCK-BRi4sv suggest that this variant may regulate colorectal cancer cell proliferation though a gastrin-independent mechanism.