Introduction of somatostatin analogs has greatly contributed to improving the prognosis of acromegaly. Although the majority of patients are effectively treated by these agents, resistance occurs in a subset of patients. So far, resistance to somatostatin has never been associated with mutations of the somatostatin receptor subtypes (sst2 and sst5) that inhibit GH secretion. Molecular analysis of genomic DNA from pituitary tumor and peripheral blood obtained from an acromegalic resistant to octreotide showed a somatic activating mutation of Gsalpha (Arg201Cys), no mutation in sst2, and one polymorphism (Pro109Ser) and one germ line mutation (Arg240Trp) in sst5. Wild-type (WT) and mutant sst5 PCR products were cloned and transfected into Chinese hamster ovary K1 cells. In Chinese hamster ovary K1 cells stably expressing mutant sst5, somatostatin-28 was less potent in inhibiting cyclic AMP levels than in WT cells. Proliferation of mutant cells exceeded that of WT by 50%. Moreover, somatostatin reduced cell growth and MAPK activity in WT but not in mutant cells in which the peptide even increased MAPK activity. We suggest that this mutation that abrogates the antiproliferative action of somatostatin and activates mitogenic pathways may be involved in the resistance to somatostatin treatment.
Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment / E. Ballarè, L. Persani, A.G. Lania, M. Filopanti, E. Giammona, S. Corbetta, S. Mantovani, M. Arosio, P. Beck-Peccoz, G. Faglia, A. Spada. - In: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. - ISSN 0021-972X. - 86:8(2001 Aug), pp. 3809-3814.
|Titolo:||Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment|
BALLARE', EMILIA (Primo)
PERSANI, LUCA (Secondo)
FAGLIA, GIOVANNI (Penultimo)
SPADA, ANNAMARIA (Ultimo)
|Parole Chiave:||Animals ; Polymorphism, Single Nucleotide ; Antineoplastic Agents, Hormonal ; Recombinant Proteins ; Humans ; Octreotide ; Drug Resistance ; Pituitary Neoplasms ; Polymerase Chain Reaction ; Transfection ; Receptors, Somatostatin ; CHO Cells ; Mitogen-Activated Protein Kinases ; Middle Aged ; Germ-Line Mutation ; Adenoma ; Amino Acid Substitution ; Female ; Acromegaly ; Cell Division ; Cricetinae|
|Settore Scientifico Disciplinare:||Settore MED/13 - Endocrinologia|
|Data di pubblicazione:||ago-2001|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1210/jc.86.8.3809|
|Appare nelle tipologie:||01 - Articolo su periodico|