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N-Terminal Proopiomelanocortin Acts as a Mitogen in Adrenocortical Tumor Cells and Decreases Adrenal Steroidogenesis

Department of Medicine, Endocrine and Diabetes Unit (M.F., S.H., I.A.H., T.K., M.Z., B.A.), Department of Orthopedics (F.J.), and Institut fuer Medizinische Strahlenkunde und Zellforschung (J.T.), University of Wurzburg, Wurzburg 97080, Germany; and IPF PharmaCeuticals GmbH (K.A.), 30625 Hannover, Germany

Address all correspondence and requests for reprints to: Martin Fassnacht, M.D., Department of Medicine, Endocrine and Diabetes Unit, University of Wurzburg, 97080 Wurzburg, Germany. E-mail: Fassnacht-M{at}medizin.uni-wuerzburg.de.

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.

This work was supported by the Deutsche Forschungsgemeinschaft (Grant Al 203/7-1, to B.A.).

Present address for J.T.: Daniel-Swarovski Research Lab, Department of Surgery, University of Innsbruck, 6020 Innsbruck, Austria.

Abbreviations: AsP, Adrenal secretory protease; bFGF, basic fibroblast growth factor; DAX-1, dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X-chromosome 1; DHEA-S, dehydroepiandrosterone sulfate; ESIMS, electrospray ionization mass spectrometry; FCS, fetal calf serum; IgG, immunoglobulin G; JNK, c-Jun N-terminal kinase; MEK, MAPK kinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide; N-POMC, N-terminal proopiomelanocortin; 17-OH-P, 17-hydroxyprogesterone; P40scc, cytochrome P450 side-chain cleavage enzyme; POMC, proopiomelanocortin; SF-1, steroidogenic factor 1; StAR, steroidogenic acute regulatory protein.

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