Somatostatin Receptor sst2 Decreases Cell Viability and Hormonal Hypersecretion and Reverses Octreotide Resistance of Human Pituitary Adenomas

被引:33
作者
Acunzo, Julie [1 ]
Thirion, Sylvie [1 ]
Roche, Catherine [1 ]
Saveanu, Alexandru [1 ,2 ,5 ]
Gunz, Ginette [1 ]
Germanetti, Anne Laure [2 ]
Couderc, Bettina [6 ]
Cohen, Richard [7 ]
Figarella-Branger, Dominique [3 ]
Dufour, Henry [4 ]
Brue, Thierry [5 ]
Enjalbert, Alain [1 ,2 ]
Barlier, Anne [1 ,2 ,5 ]
机构
[1] Univ Mediterranee, Inst Federatif Jean Roche, CNRS, Ctr Res Neurobiol Neurophysiol Marseille,UMR 6231, Marseille, France
[2] Univ Timone, Ctr Hosp, Biochem & Mol Biol Lab, Marseille, France
[3] Univ Timone, Ctr Hosp, Neuropathol Lab, Marseille, France
[4] Univ Timone, Ctr Hosp, Dept Neurosurg, Marseille, France
[5] Univ Timone, Ctr Hosp, Dept Endocrinol, Marseille, France
[6] Univ Toulouse, Inst Claudius Regaud, EA 3035, Toulouse, France
[7] Univ Lyon 1, Hop Edouard Herriot, Hosp Civils Lyon, ISPB,TRI2B,UPSP 2007 03 135, Lyon, France
关键词
D O I
10.1158/0008-5472.CAN-08-1857
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
In human somatotroph adenomas, growth hormone (GH) hypersecretion can be inhibited by somatostatin analogues such as octreotide. Unfortunately, serum GH levels reach normal values in only 60% of treated patients. The decreased sensitivity to octreotide is strongly related to a lower expression of somatostatin receptor sst2. In this present study, the sst2 gene was transferred by an adenoviral vector (Ad-sst2) in human somatotroph (n = 7) and lactotroph (n = 2) adenomas in vitro. Sst2 mRNA levels and sst2 immunostaining dramatically increased after infection. Ten days after infection at 20 multiplicity of infection (MOI), sst2 gene transfer decreased cell viability from 19% to 90% by caspase-dependent apoptosis. At low viral doses (5 MOI), Ad-sst2 decreased GH or prolactin (PRL) basal secretion and mRNA expression. Somatotroph tumors were classified in three groups according to their octreotide sensitivity. Four days after infection by 5 MOI Ad-sst2, the maximal GH suppression by octreotide increased from 31% to 57% in the octreotide partially resistant group and from 0% to 27% in the resistant ones. In the octreotide-sensitive group, EC50 values significantly decreased from 1.3 x 10(-11) to 6.6 x 10(-13) mol/L without improving maximal GH suppression. Finally, lactotroph tumors, nonresponding to octreotide in basal conditions, became octreotide sensitive with a maximal PRL suppression of 43% at 10(-8) mol/L. Therefore, sst2 reexpression is able to improve octreotide sensitivity. Sst2 gene transfer may open new theapeutic strategies in treatment combined with somatostatin analogues. [Cancer Res 2008;68(24):.1.0163-70]
引用
收藏
页码:10163 / 10170
页数:8
相关论文
共 38 条
[1]   Identification of proliferating human anterior pituitary adenoma cells in vitro [J].
Atkin, SL ;
Burnett, HE ;
Landolt, AM ;
Green, VL ;
Hipkin, LJ ;
White, MC .
NEUROLOGICAL RESEARCH, 1997, 19 (04) :420-425
[2]   Relevance of coexpression of somatostatin and dopamine D2 receptors in pituitary adenomas [J].
Aveanu, A. S. ;
Jaquet, P. ;
Brue, T. ;
Barher, A. .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2008, 286 (1-2) :206-213
[3]   Impact of gsp oncogene on the expression of genes coding for Gsα, Pit-1, Gi2α, and somatostatin receptor 2 in human somatotroph adenomas:: Involvement in octreotide sensitivity [J].
Barlier, A ;
Pellegrini-Bouiller, I ;
Gunz, G ;
Zamora, AJ ;
Jaquet, P ;
Enjalbert, A .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1999, 84 (08) :2759-2765
[4]   Pronostic and therapeutic consequences of Gsα mutations in somatotroph adenomas [J].
Barlier, A ;
Gunz, G ;
Zamora, AJ ;
Morange-Ramos, I ;
Figarella-Branger, D ;
Dufour, H ;
Enjalbert, A ;
Jaquet, P .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1998, 83 (05) :1604-1610
[5]   Selective regulation of somatostatin receptor subtype signaling: Evidence for constitutive receptor activation [J].
Ben-Shlomo, Anat ;
Pichurin, Oxana ;
Barshop, Nicole J. ;
Wawrowsky, Kolja A. ;
Taylor, John ;
Culler, Michael D. ;
Chesnokova, Vera ;
Liu, Ning-Ai ;
Melmed, Shlomo .
MOLECULAR ENDOCRINOLOGY, 2007, 21 (10) :2565-2578
[6]   Inhibition of growth and metastatic progression of pancreatic carcinoma in hamster after somatostatin receptor subtype 2 (sst2) gene expression and administration of cytotoxic somatostatin analog AN-238 [J].
Benali, N ;
Cordelier, P ;
Calise, D ;
Pagès, P ;
Rochaix, P ;
Nagy, A ;
Estève, JP ;
Pour, PM ;
Schally, AV ;
Vaysse, N ;
Susini, C ;
Buscail, L .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (16) :9180-9185
[7]  
BERTHERAT J, 1993, J CLIN ENDOCR METAB, V77, P1577, DOI 10.1210/jc.77.6.1577
[8]   Recent developments in constitutive receptor activity and inverse agonism, and their potential for GPCR drug discovery [J].
Bond, RA ;
IJzerman, AP .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2006, 27 (02) :92-96
[9]  
Buscail L, 1996, CANCER RES, V56, P1823
[10]   STIMULATION OF TYROSINE PHOSPHATASE AND INHIBITION OF CELL-PROLIFERATION BY SOMATOSTATIN ANALOGS - MEDIATION BY HUMAN SOMATOSTATIN RECEPTOR SUBTYPES SSTR1 AND SSTR2 [J].
BUSCAIL, L ;
DELESQUE, N ;
ESTEVE, JP ;
SAINTLAURENT, N ;
PRATS, H ;
CLERC, P ;
ROBBERECHT, P ;
BELL, GI ;
LIEBOW, C ;
SCHALLY, AV ;
VAYSSE, N ;
SUSINI, C .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (06) :2315-2319