Possible Relevance between Prohormone Convertase 2 Expression and Tumor Growth in Human Adrenocorticotropin-Producing Pituitary Adenoma

Context: Methods for preoperative diagnosis of prohormone convertase 2 (PC2)-positive ACTH-producing pituitary adenomas(APPAs) have not been established. Also, their characteristics are not evident. Objective: This study was designed to understand the meaning of plasma alpha MSH levels and the role of cell proliferation-signaling molecules in PC2-positive APPAs. Patients and Main Outcome Measures: Nineteen human APPAs (four males and 15 females) were examined for the expression of PC2, phosphorylated ERK1/2, phosphorylated Akt1/2/3 (p-Akt) and receptor tyrosine kinases. alpha MSH was measured in extracted plasma from 17 APPA patients and 30 healthy volunteers. Results: Nine adenomas (47.4%) were immunopositive for PC2 and were large and invasive in nature. In all normal controls and eight PC2-negative cases, plasma alpha MSH was undetectable, whereas in four PC2-positive cases, it was detected at abnormally higher levels. Eight adenomas (42.1%) were immunopositive for both PC2 and p-Akt, and seven others (36.8%) were immunonegative for both, suggesting significant coexpression of PC2 and p-Akt in tumors. Quantitative RT-PCR revealed that PC2 expression is associated with phosphorylation of Akt but not with its gene expression. Most APPAs expressed receptor tyrosine kinases, but membrane-bound receptors could not be identified. Conclusions: Our study suggests that PC2 expression and Akt phosphorylation are related at the molecular level, resulting in a change in cell cycle and an increase in pituitary adenoma size. An elevation of plasma alpha MSH could conjecture the activation of the phosphatidylinositol 3/Akt cascade in PC2-positive APPAs and may become a valuable clinical marker of tumor growth in Cushing's disease. (J Clin Endocrinol Metab 95: 4003-4011, 2010)