Up-regulation of somatostatin receptors by epidermal growth factor and gastrin in pancreatic cancer cells.
Interactions between growth factor receptor systems may be important in the regulation of cell growth. The proliferation of pancreatic tumor AR42J cells has been shown to be stimulated by Epidermal growth factor (EGF) and gastrin and inhibited by somatostatin. To analyze the interaction between these different peptides, we explored the influence of EGF and gastrin on the somatostatin receptors. Treatment of AR42J cells with 10 nM EGF or gastrin for 24 hr increased specific binding of [125I] Tyr3SMS to 131 and 147% of that in control cells, respectively. The effect of peptides on [125I]Tyr3SMS binding was time- and dose-dependent, with half-maximal effect at 0.2 +/- 0.03 nM EGF and 0.3 +/- 0.15 nM gastrin. Scatchard plots revealed an increase in somatostatin receptor number of 27 and 80% after 48 hr of treatment with EGF and gastrin, respectively, without any change in receptor affinity. The increase in somatostatin receptor density was accompanied by the enhancement of biological responses to somatostatin. In cells pretreated with EGF or gastrin, the potency of somatostatin for inhibiting vasoactive intestinal peptide-stimulated cAMP content was increased 2-fold as that of somatostatin analog, SMS, for inhibiting cell proliferation. Furthermore, the efficiency of SMS as antiproliferative agent was greatly increased. Vasoactive intestinal peptide or forskolin did not modify [125I]Tyr3SMS binding of control or treated cells. The phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) did not affect [125I]Tyr3SMS binding. On the other hand, cycloheximide completely blocked the increase in [125I]Tyr3SMS binding induced by EGF and gastrin.(ABSTRACT TRUNCATED AT 250 WORDS)
Vidal
C
C
INSERM U 151, Institut Louis Bugnard, CHU Rangueil, Toulouse, France.
Rauly
I
I
Zeggari
M
M
Delesque
N
N
Esteve
J P
JP
Saint-Laurent
N
N
Vaysse
N
N
Susini
C
C
D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D017931:DNA Primers; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005755:Gastrins / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015282:Octreotide / Q000031:analogs & derivatives / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D017931:DNA Primers; D005755:Gastrins; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C045210:3-Tyr-octreotide; D004815:Epidermal Growth Factor; D003513:Cycloheximide; D000242:Cyclic AMP; D011493:Protein Kinase C; D015282:Octreotide