Possible relevance between prohormone convertase 2 expression and tumor growth in human adrenocorticotropin-producing pituitary adenoma.
BACKGROUND
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 alphaMSH levels and the role of cell proliferation-signaling molecules in PC2-positive APPAs.


METHODS
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. alphaMSH 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 alphaMSH 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 alphaMSH 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.
Iino
Kazumi
K
Second Division, Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama Higashi-ku, Hamamatsu 431-3192, Japan.
Oki
Yutaka
Y
Yamashita
Miho
M
Matsushita
Fumie
F
Hayashi
Chiga
C
Yogo
Kosuke
K
Nishizawa
Shigeru
S
Yamada
Shozo
S
Maekawa
Masato
M
Sasano
Hironobu
H
Nakamura
Hirotoshi
H
D049913:ACTH-Secreting Pituitary Adenoma / Q000235:genetics / Q000378:metabolism*; D000236:Adenoma / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D045706:Proprotein Convertase 2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000521:alpha-MSH / Q000097:blood*
D012333:RNA, Messenger; D000521:alpha-MSH; D048052:Mitogen-Activated Protein Kinase 3; D045706:Proprotein Convertase 2