N-terminal proopiomelanocortin acts as a mitogen in adrenocortical tumor cells and decreases adrenal steroidogenesis.
There is evidence that proopiomelanocortin (POMC)-derived peptides other than ACTH are involved in pituitary-dependent adrenal growth. We have synthesized the human N-terminal POMC fragment 1-28-POMC with the disulfide bridges in the correct position between cysteine residues 2-24 and 8-20 and studied the activity of these peptides in adrenocortical tumor cells in vitro. 1-28-POMC stimulated cell proliferation in human NCI-h295 and mouse Y-1 adrenal cancer cell lines and also in primary cultures of bovine adrenocortical cells in a concentration-dependent manner. 1-28-POMC led to rapid activation of the MAPKs extracellular signal-regulated kinases-1 and -2, but not c-Jun N-terminal kinase and p38, pathways. Steroid hormone production (cortisol, 17-hydroxyprogesterone, and dehydroepiandrosterone sulfate) in NCI-h295 cells was decreased by 1-28-POMC in a concentration-dependent fashion. However, protein levels of important regulators of steroidogenesis [steroidogenic factor-1, DAX-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X-chromosome 1), steroidogenic acute regulatory protein, and cytochrome P450 side-chain cleavage enzyme] remained unaffected by 1-28-POMC treatment. Our results provide evidence that synthetic 1-28-POMC induces adrenal tumor cell proliferation, inhibits adrenal steroidogenesis, and mediates its action by signaling via the extracellular signal-regulated kinase pathway. The distinct roles of 1-28-POMC and ACTH in the regulation of adrenal growth and steroidogenesis suggest that the adrenal cortex is under the dual opposing control of fragments from the same mother peptide POMC.
Fassnacht
Martin
M
Department of Medicine, Endocrine and Diabetes Unit, University of Wurzburg, Wurzburg 97080, Germany. Fassnacht-M@medizin.uni-wuerzburg.de
Hahner
Stefanie
S
Hansen
Immo A
IA
Kreutzberger
Tanja
T
Zink
Martina
M
Adermann
Knut
K
Jakob
Franz
F
Troppmair
Jakob
J
Allolio
Bruno
B
D019326:17-alpha-Hydroxyprogesterone / Q000378:metabolism; D000302:Adrenal Cortex / Q000187:drug effects; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis*; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D000305:Adrenal Cortex Hormones; D008934:Mitogens; D010446:Peptide Fragments; D019314:Dehydroepiandrosterone Sulfate; D011333:Pro-Opiomelanocortin; D019326:17-alpha-Hydroxyprogesterone; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006854:Hydrocortisone