Ruolo delle diverse subunità regolatorie della PKA nella regolazione della proliferazione di cellule endocrine ed endocrino-relate

The two regulatory subunits (R1 and R2) of PKA are differentially expressed in several cancer cell lines and studies indicate distinct roles for these subunits in growth control. In recent years, mutations of genes involved in cAMP signalling and resulting in the constitutive activation of cAMP formation have been identified as cause of endocrine neoplasia. In particular, activating mutations of the ? subunit of the stimulatory G protein gene have been found in about 30-40% of GH secreting pituitary adenomas and in subsets of thyroid, adrenocortical, ovarian and testicular Leydig cell tumors, while mutations of the PKA regulatory subunit 1A gene (PRKAR1A) have been identified in patients with Carney complex, a familial multiple endocrine neoplasia syndrome. This thesis evaluated the expression of the different PKA regulatory subunits (R1A, R2A, R2B) in human pituitary adenomas, cortisol-secreting adrenocortical tumors and melanomas, as well as the effects of selective subunit activation on cell proliferation. Our data indicate that altered PKA R1/R2 ratio characterize most endocrine tumors, when compared with the normal counterpart, and that pharmacological and genetic manipulations able to revert this unbalanced expression are able to induce significant anti-proliferative and pro-apoptotic effectis in human tumoral cells.