Sethi T, Herget T, Wu SV, Walsh JH, Rozengurt E.. CCKA and CCKB receptors are expressed in small cell lung cancer lines and mediate Ca2+ mobilization and clonal growth. Cancer Res 53: 5208-5213 (original) (raw)

Abstract

Castrili, cholecystokinin (CCK), and CCK-related peptides comprise a Imimonili family characterized by an identical carboxy-terminal amino acid sequence, a domain critical for receptor binding. The addition of gastrin to small cell lung cancer (SCLC) cells causes a rapid and transient increase in the intracellular concentration of calcium i|(';r'|,i. Further more, gastrin acts as a direct growth factor through CCKn/gastrin recep tors. We report here that the expression of the mRNA coding for CCKu/ gastrin receptors correlates with the responsiveness of SCLC cells to gastrin in terms of (';r ' mobilization and stimulation of clonal growth in semisolid medium. The GLC19 SCLC cell line had no detectable expres sion of CCKn/gastrin receptor mRNA. Accordingly, gastrin (1-100 IIMIdid not cause any measurable increase in |('¡i '' |¡-In contrast, the addition of cholecystokinin residues 26â€"33(CCK-8) caused a rapid and transient increase in |< '¡r'1 ], in this cell line. CCK-8 mobilized « ;i '' in a dosedependent manner in the nanomolar range (half-maximal stimulatory concentration = 12 nvi). Furthermore, the selective CCKA antagonist CAM-1481 inhibited the increase in |(':i-'-|, induced by CCK-8 (halfmaximal inhibitory concentration = 3 n>i) in GLC19 but not in H510 cells. The selective CCKn/gastrin antagonist blocked the increase in |(;r ' |, induced by CCK-8 (half-maximal inhibitory concentration = 80 pM) in H510 but not in GLC19 cells. Thus, the effects of CCK-8 are mediated through CCKA receptors in GLC19 cells and via CCKB/gastrin receptors in H510 cells. CCK-8 markedly stimulated colony formation in GLC19 cells in a dose-dependent manner in the nanomolar range, whereas over the same concentration range, gastrin had no effect on clonal growth. CAM-1481 inhibited the CCK-stimulated colony formation in GLC19 but not in H510 cells. Our results show, for the first time, that CCKA receptors can mediate (a'' mobilization and growth in SCLC cells and that SCLC cells express two distinct functional CCK receptor subtypes.

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