Bombesin-mediated AP-1 activation in a human gastric cancer (SIIA)

H. J. Kim, B. M. Evers, Y. Guo, N. A. Banker, M. R. Hellmich, Jr Townsend

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18 Scopus citations


Background. Bombesin, a gut tetradecapeptide homologous to the mammalian gastrin-releasing peptide (GRP), stimulates the growth of the human gastric cancer line SIIA through specific GRP receptors (GRP-Rs); the cellular mechanisms are not known. The purpose of our study was to (1) confirm functional GRP-R in SIIA and (2) determine whether bombesin alters the expression and binding activity of the AP-1 transcription factors, c-jun and jun-B. Methods. SIIA cells were treated with bombesin, and intracellular calcium mobilization was measured by means of fura-2 spectrofluorometry. To assess changes in c-jun and jun-B, RNA and protein were extracted for Northern and Western blots, respectively; nuclear protein was extracted for gel mobility shifts to determine AP-1 binding activity. Results. SIIA cells mobilized intracellular calcium in response to bombesin, exhibiting a functional cell-surface GRP-R. Bombesin treatment increased expression op both c-jun and jun-B mRNA by 0.5 hours, with maximal expression at 1 hour; concomitant increases in steady-state levels of c-Jun and JunB protein were identified. Moreover, bombesin increased binding of the AP-1 proteins as shown by gel shifts. Conclusions. The SIIA human gastric cancer possesses functional GRP-R coupled to the calcium second messenger pathway. Further, bombesin stimulates expression of c-jun and jun-B mRNA and protein and increases binding activity of AP-1 proteins. Delineating the cellular pathways involved in bombesin-mediated gene activation will provide important insights into the mechanisms responsible for normal and neoplastic gut growth.

Original languageEnglish
Pages (from-to)130-137
Number of pages8
Issue number2
StatePublished - 1996

Bibliographical note

Funding Information:
BOMBESIN,A TETRADECAPEPTIDEh omologous to the mammalian 27-amino acid gastrin-releasing peptide (GRP), is found widely distributed throughout the respiratory tract, the central nervous system, and the gastrointestinal tract, l Bombesin and GRP act as physiologic "on switches" to stimulate the release of gastrointestinal hormones and the growth of normal gastrointestinal tissues. 24 In addition, bombesin acts as a potent mitogen to stimulate the growth of small cell lung cancers, breast cancers, and gut neoplasms, specifically gastric cancers.5, 6 Bombesin acts through its specific receptor, the GRP-receptor (GRP-R), which is found throughout the gut, the central nervous system, and numerous neoplasms. 7 The GRP-R contains a seven-transmembrane Supported by grants from The National Institutes of Health (PO1 DK35608, 1RO1 DK 48345, 5T32 DK07639, R29 AG10885) and the James E. Thompson Molecular Biology Laboratory for Surgical Research. Presented at the Fifty-seventhA nnual Meeting of the Society of University Surgeons, Washington, D.C., Feb. 8-10, 1996. Reprint requests: Courtney M. Townsend,Jr., MD, Department of Surgery, The Universityo f Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0527. Copyright 9 1996 by Mosby-YearB ook, Inc. 0039-6060/96/$5.00 + 0 11/6/73516 domain and is coupled to G proteins. Binding by either bombesin or GRP leads to mobilization of intraceilular calcium (\[Ca2+\]i) and eventual downstream activation of various nuclear transcription factors; the precise transduction pathways that transmit the signal from the cell surface to the nucleus are not known, s Moreover, the exact transcription factors activated by bombesin have not been determined in a number of cell systems. The large family of AP-1 transcription factors, constituted by products encoded by members ofthejun (e.g., c-Jun and JunB) and fos families, bind the consensus AP-1 site (TGACTCA) and have been implicated as possible mediators coupling signals at the cell surface to the physiologic responses of cellular growth and differentiation. 919 We are interested in determining the mechanisms responsible for bombesin-mediated growth of gastric cancers and whether AP-1 gene activation plays a role in this process. These studies, however, have been hampered by the lack of a suitable in vitro cell model that possesses a native GRP-R. The human gastric adenocarcinoma SIIA, which was established in our laboratory, 13 possesses a native GRP-R that binds bombesin with high affinity; its growth is significantly stimulated in response to bombesin. The exact cellular mechanisms responsible for this bombesin-

ASJC Scopus subject areas

  • Surgery


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