Dopamine (DA) therapy of non-functioning pituitary adenomas (NFA) can result in tumor stabilization and shrinkage. However, this effect is not always apparent and the mechanism of action is still unknown. Previous evidence showed that DA inhibits pituitary Vascular Endothelial Growth Factor expression (VEGF), that, in turn, is related to pituitary tumor growth. Our study aimed at clarifying whether VEGF secretion modulation might mediate the effects of DA agonists and chimeric compounds interacting with both DA receptor 2 (DR2) and somatostatin receptor (SSTR) 2 and 5 on cell proliferation in human NFA primary cultures. We assessed DR2, SSTR2 and SSTR5 expression, both at mRNA and protein level, as well as the in vitro effects on VEGF secretion and on cell viability of a selective DR2 agonist, cabergoline (Cab), and of the chimeric compound BIM-23A760, which interacts with DR2, SSTR2 and 5. Nine NFA were examined by RT-PCR and by microscopy immunofluorescence for expression of α-subunit, DR2, SSTR2 and 5. Primary cultures were tested with Cab and with BIM-23A760. All NFA samples expressed α-sub, while DR2 and SSTR2 were expressed in 5 and SSTR5 in 2 samples. In DR2 expressing tumors, Cab (but not BIM-23A760) significantly reduced cell viability (−18%; P<0.05) and VEGF secretion (−15%; P<0.05). These effects were counteracted by treatment with the DA antagonist sulpiride. In addition, the antiproliferative effects of Cab were completely blocked by co-treatment with VEGF. Our data demonstrate that Cab, but not the chimeric SSTR/DR compound, via DR2 can inhibit cell viability by reducing VEGF secretion in a selected group of NFA, providing support for the employment of DA agonists in medical therapy of NFA expressing DR2. Moreover, these data further support the hypothesis that pituitary VEGF expression is under dopaminergic control and underline the importance of an accurate biomolecular analysis of pituitay adenomas.
Dopamine receptor 2 activation reduces cells viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion
ZATELLI, Maria Chiara;TAGLIATI, Federico;LUCHIN, Andrea;AMBROSIO, Maria Rosaria;BONDANELLI, Marta;DEGLI UBERTI, Ettore
2008
Abstract
Dopamine (DA) therapy of non-functioning pituitary adenomas (NFA) can result in tumor stabilization and shrinkage. However, this effect is not always apparent and the mechanism of action is still unknown. Previous evidence showed that DA inhibits pituitary Vascular Endothelial Growth Factor expression (VEGF), that, in turn, is related to pituitary tumor growth. Our study aimed at clarifying whether VEGF secretion modulation might mediate the effects of DA agonists and chimeric compounds interacting with both DA receptor 2 (DR2) and somatostatin receptor (SSTR) 2 and 5 on cell proliferation in human NFA primary cultures. We assessed DR2, SSTR2 and SSTR5 expression, both at mRNA and protein level, as well as the in vitro effects on VEGF secretion and on cell viability of a selective DR2 agonist, cabergoline (Cab), and of the chimeric compound BIM-23A760, which interacts with DR2, SSTR2 and 5. Nine NFA were examined by RT-PCR and by microscopy immunofluorescence for expression of α-subunit, DR2, SSTR2 and 5. Primary cultures were tested with Cab and with BIM-23A760. All NFA samples expressed α-sub, while DR2 and SSTR2 were expressed in 5 and SSTR5 in 2 samples. In DR2 expressing tumors, Cab (but not BIM-23A760) significantly reduced cell viability (−18%; P<0.05) and VEGF secretion (−15%; P<0.05). These effects were counteracted by treatment with the DA antagonist sulpiride. In addition, the antiproliferative effects of Cab were completely blocked by co-treatment with VEGF. Our data demonstrate that Cab, but not the chimeric SSTR/DR compound, via DR2 can inhibit cell viability by reducing VEGF secretion in a selected group of NFA, providing support for the employment of DA agonists in medical therapy of NFA expressing DR2. Moreover, these data further support the hypothesis that pituitary VEGF expression is under dopaminergic control and underline the importance of an accurate biomolecular analysis of pituitay adenomas.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
