The biological and therapeutic importance of gastrin gene expression in pancreatic adenocarcinomas.
The gastrin gene is expressed widely in pancreatic adenocarcinomas and the study aimed to assess its role in both the resistance of cancer cells to apoptosis and the sensitivity of cells to chemotherapeutic agents. Two human pancreatic cell lines, PAN1 and BXPC3, expressed gastrin at both the RNA and protein levels and are shown to be representative of human pancreatic adenocarcinomas in terms of gastrin expression. Inhibition of endogenous gastrin production by tumor cells was achieved with neutralizing gastrin antiserum and transfection with a gastrin antisense plasmid. Gastrin antiserum synergized with both taxotere and gemcitabine in inhibiting the in vitro growth of the PAN1 cell line with the inhibitory effect of the antiserum increasing from 12.7% to 70.2% with taxotere (P < 0.05) and 28.6% with gemcitabine (P < 0.01) after controlling for the effects of the cytotoxics. Synergy was only achieved with taxotere in BXPC3 cells with the inhibitory effect of gastrin antiserum increasing from 22.9% to 50.0% (P < 0.005). Cells transfected with gastrin antisense had reduced in vitro growth in low serum conditions and were poorly tumorigenic in nude mice at an orthotopic site. Gastrin antisense-transfected PAN1 cells had increased sensitivity to the antiproliferative effects of both gemcitabine (IC50 of > 100 microg/ml reduced to 0.1 microg/ml) and taxotere (IC50 of 20 microg/ml reduced to < 0.01 microg/ml) when compared with vector controls. The increased sensitivity of PAN1 antisense coincided with increased caspase-3 activity and reduced protein kinase B/Akt phosphorylation in response to both gemcitabine and taxotere. Gastrin gene circumvention may be an optimal adjunct to chemotherapeutic agents, such as taxotere and gemcitabine, in pancreatic adenocarcinoma.
Academic Unit of Cancer Studies, University of Nottingham, Nottingham, United Kingdom.
Joseph C
JC
Harris
Andrew D
AD
Gilliam
Andrew J
AJ
McKenzie
Sean A
SA
Evans
Anna M
AM
Grabowska
Philip A
PA
Clarke
Daniel F
DF
McWilliams
Sue A
SA
Watson
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D016373:DNA, Antisense / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077143:Docetaxel; D005755:Gastrins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D010766:Phosphorylation; D011498:Protein Precursors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D043823:Taxoids / Q000494:pharmacology; D014162:Transfection; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D016373:DNA, Antisense; D005755:Gastrins; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C013706:big gastrin; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine