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Human somatostatin receptor subtypes in acromegaly: distinct patterns of messenger ribonucleic acid expression and
1Interactions Cellulaires Neuroendocrines, UMR 6544, Centre National de la Recherche Scientifique, Institut Fédératif Jean Roche, Faculté de Médecine Nord, Marseille, France. jaquet.p@jean-roche.univ.mrs.fr
Abstract:
Recently, studies using somatostatin (SRIF) analogs preferential for either the SRIF receptor 2 (SSTR2) or the SSTR5 subtype demonstrated a variable suppression of GH and PRL release from GH-secreting human adenomas. These data suggested the concept of SSTR subtype specificity in such tumors. In the present study the quantitative expression of messenger ribonucleic acid (mRNA) for the 5 SSTR subtypes and the inhibitory effects of SRIF14; SRIF28; octreotide; the SSTR2-preferential analog, BIM-23197; and the SSTR5-preferential analog, BIM-23268, on GH and PRL secretion were analyzed in cells cultured from 15 acromegalic tumors. RT-PCR analysis revealed a consistent pattern of SSTR2 and SSTR5 mRNA expression. SSTR5 mRNA was expressed at a higher level (1052 +/- 405 pg/pg glyceraldehyde-3-phosphate dehydrogenase) than SSTR2 mRNA (100 +/- 30 pg/pg glyceraldehyde-3-phosphate dehydrogenase). However, only SSTR2 mRNA expression correlated with the degree of GH inhibition induced by SRIF14, SRIF28, and BIM-23197. The SSTR5-preferential compound inhibited GH release in only 7 of 15 cases. In cells cultured from the 10 mixed adenomas that secreted both GH and PRL, RT-PCR analysis revealed a consistent coexpression of SSTR5, SSTR2, and SSTR1 mRNA. In all cases SRIF14, SRIF28, and the SSTR5-preferential analog, BIM-23268, significantly suppressed PRL secretion, with a mean maximal inhibition of 48 +/- 4%. In contrast, the SSTR2-preferential analogs, BIM-23197 and octreotide, were effective in suppressing PRL in only 6 of 10 cases. In cells cultured from adenomas taken from patients partially responsive to the SRIF analog, octreotide, partial additivity in suppressing both GH and PRL secretion was observed when the SSTR2- and SSTR5-preferring analogs, BIM-23197 and BIM-23268, were tested in combination. Our data show a highly variable ratio of the SSTR2 and SSTR5 transcripts, according to tumors. The SSTR2-preferring compound consistently inhibits GH release, whereas the SSTR5-preferring compound is the main inhibitor of PRL secretion. When both drugs are combined, the partial additivity observed in mixed GH- plus PRL-secreting adenomas may be of interest in the therapeutic approach of such tumors.
Insights
Somatostatin receptor (SSTR) subtype expression varies in acromegalic tumors. SSTR2 analogs best inhibit growth hormone (GH), while SSTR5 analogs best inhibit prolactin (PRL), suggesting targeted therapies for mixed adenomas.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Somatostatin (SRIF) analogs show variable efficacy in suppressing growth hormone (GH) and prolactin (PRL) from GH-secreting adenomas.
- This variability suggests somatostatin receptor (SSTR) subtype specificity in these tumors.
Purpose of the Study:
- To quantitatively analyze the expression of five SSTR subtypes (mRNA) in human acromegalic tumors.
- To evaluate the inhibitory effects of various SRIF analogs on GH and PRL secretion, assessing SSTR subtype specificity.
Main Methods:
- Quantitative mRNA expression analysis of SSTR subtypes using RT-PCR in cells from 15 acromegalic tumors.
- In vitro assessment of GH and PRL secretion inhibition by SRIF14, SRIF28, octreotide, SSTR2-preferential BIM-23197, and SSTR5-preferential BIM-23268.
Main Results:
- Consistent SSTR2 and SSTR5 mRNA expression observed, with higher SSTR5 than SSTR2 levels.
- SSTR2 mRNA expression correlated with GH inhibition by SRIF14, SRIF28, and BIM-23197; BIM-23268 inhibited GH in only 7/15 cases.
- SSTR5-preferential BIM-23268 and SRIF analogs significantly suppressed PRL in mixed adenomas (48% inhibition), while SSTR2 analogs were less effective (6/10 cases).
- Partial additivity in GH and PRL inhibition was noted when combining SSTR2- and SSTR5-preferential analogs.
Conclusions:
- Tumor-specific ratios of SSTR2 and SSTR5 transcripts influence analog efficacy.
- SSTR2-preferring compounds primarily inhibit GH release, whereas SSTR5-preferring compounds are key for PRL inhibition.
- Combination therapy with SSTR2 and SSTR5 analogs may offer a therapeutic strategy for mixed GH- and PRL-secreting adenomas.