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Volume 271, Number 46, Issue of November 15, 1996 pp. 29453-29460
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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[D-Arg¹,D-Trp^5,7,9,Leu¹¹]Substance P Coordinately and Reversibly Inhibits Bombesin- and Vasopressin-induced Signal Transduction Pathways in Swiss 3T3 Cells

(Received for publication, February 12, 1996, and in revised form, August 30, 1996)

From the Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom

The novel substance P (SP) analogue, [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP like [D-Arg¹,D-Phe⁵,D-Trp^7,9,Leu¹¹]SP inhibited DNA synthesis induced by bombesin, vasopressin, and bradykinin, but did not interfere with the mitogenic response induced by other growth factors or pharmacological agents in Swiss 3T3 cells. [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP reversibly inhibited bombesin-induced DNA synthesis, causing a 6-fold greater rightward shift in the bombesin dose response than [D-Arg¹,D-Phe⁵,D-Trp^7,9,Leu¹¹]SP at identical concentrations (10 µM). We found that the new, more potent, SP analogue coordinately and reversibly inhibited bombesin-induced Ca²⁺ mobilization and protein kinase C (PKC) and mitogen-activated protein (MAP) kinase activation. The dose-response curves for bombesin-induced Ca²⁺ mobilization and MAP kinase activation were similarly displaced (51- and 40-fold, respectively) by [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP. In addition, [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP reversibly inhibited bombesin-induced tyrosine phosphorylation of M_r 110,000-130,000 and 70,000-80,000 bands as well as p125 focal adhesion kinase. [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP also reversibly and coordinately inhibited vasopressin-induced Ca²⁺ mobilization, PKC stimulation, MAP kinase activation, tyrosine phosphorylation, and DNA synthesis in Swiss 3T3 cells. Surprisingly, deletion of the terminal Leu of [D-Arg¹,D-Phe⁵,D-Trp^7,9,Leu¹¹]SP to yield [D-Arg¹,D-Phe⁵,D-Trp^7,9]SP^1-10 resulted in a selective loss of inhibitory activity of this analogue against bombesin- but not vasopressin-stimulated DNA synthesis, Ca²⁺ mobilization, and MAP kinase activation. Collectively, these results suggest that SP analogues act at the receptor level to coordinately and reversibly antagonize bombesin- or vasopressin-induced signal transduction in Swiss 3T3 cells.

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