PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma.

Abstract

Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF) action through proteolysis of IGF-binding protein (IGFBP)-4. In experimental animals, PAPP-A accelerates ovarian tumor growth by this mechanism. To investigate the effect of PAPP-A in humans, we compared serum and ascites from 22 women with ovarian carcinoma. We found that ascites contained 46-fold higher PAPP-A levels as compared to serum (P < 0.001). The majority (80%) of PAPP-A was enzymatically active. This is supported by the finding that ascites contained more cleaved than intact IGFBP-4 (P < 0.03). Ascites was more potent than serum in activating the IGF-I receptor (IGF-IR) in vitro (+31%, P < 0.05); in 8 of 22 patients by more than two-fold. In contrast, ascites contained similar levels of immunoreactive IGF-I, and lower levels of IGF-II (P < 0.001). Immunohistochemistry demonstrated the presence of IGF-IR in all but one tumor, whereas all tumors expressed PAPP-A, IGFBP-4, IGF-I and IGF-II. Addition of recombinant PAPP-A to ascites increased the cleavage of IGFBP-4 and enhanced IGF-IR activation (P < 0.05). In conclusion, human ovarian tumors express PAPP-A, IGFBP-4 and IGFs and these proteins are also present in ascites. We suggest that both soluble PAPP-A in ascites and tissue-associated PAPP-A serve to increase IGF bioactivity and, thereby, to stimulate IGF-IR-mediated tumor growth.

• Authors: Jacob Thomsen, Rikke Hjortebjerg, Ulrick Espelund, Gitte Ørtoft, Poul Vestergaard, Nils E Magnusson, Cheryl A Conover, Trine Tramm, Henrik Hager, Claus Høgdall, Estrid Høgdall, Claus Oxvig, Jan Frystyk
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 31 Pg. 32266-78 (Oct 13 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26336825 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• IGF1 protein, human
• IGF1R protein, human
• IGF2 protein, human
• Insulin-Like Growth Factor Binding Protein 4
• Receptors, Somatomedin
• Insulin-Like Growth Factor I
• Insulin-Like Growth Factor II
• Receptor, IGF Type 1
• Pregnancy-Associated Plasma Protein-A
• PAPPA protein, human

Topics

• Aged
• Ascitic Fluid (enzymology)
• Carcinoma (enzymology)
• Case-Control Studies
• Denmark
• Female
• HEK293 Cells
• Humans
• Insulin-Like Growth Factor Binding Protein 4 (metabolism)
• Insulin-Like Growth Factor I (metabolism)
• Insulin-Like Growth Factor II (metabolism)
• Middle Aged
• Ovarian Neoplasms (enzymology)
• Pregnancy-Associated Plasma Protein-A (metabolism)
• Receptor, IGF Type 1
• Receptors, Somatomedin (genetics, metabolism)
• Signal Transduction
• Transfection
• Up-Regulation