title: ACTH 1-24 inhibits proliferation of adrenocortical tumors in vivo.
abstract: OBJECTIVE
  Although several lines of evidence suggest that the overall effects of the ACTH receptor, melanocortin 2 receptor (MC2-R), mediated signal transduction on adrenocortical growth and tumorigenesis are anti-proliferative, activation of MC2-R induces mitogens like jun, fos, and myc and activates the MAPK pathway. In vivo, potential effects of endogenous ACTH on adrenal tumori-genesis can not be separated from effects of other POMC derived peptides.
  
  
  METHODS
  Murine adrenocortical tumor cells that lack MC2-R expression (Y6(pcDNA)) and Y6 cells stablely transfected with MC2-R (Y6(MC2-R)) were generated. Presence of functional MC2-R was demonstrated by RT-PCR and Western blot using an antibody for phosphorylated CREB. As a syngenic tumor model, LaHeF1/J mice simultaneously received 10(7) Y6(MC2-R) and Y6(pcDNA) subcutaneously, giving rise to MC2-R positive and negative tumors within the same animal. Animals were treated for 3 weeks in groups of 12 according to the following schedule: group A, control animals receiving saline injection; group B, animals receiving 5.7 ng/injection of a slow release formula of ACTH 1-24 administered i.p. three times a week (aiming at a low physiologic dose); and group C, animals receiving 57 ng/injection of ACTH 1-24 (high physiological dose).
  
  
  RESULTS
  Twenty days of ACTH 1-24 treatment did not significantly affect corticosterone levels, endogenous ACTH levels or adrenal and thymus weight compared with saline injection. However, ACTH 1-24 treatment of group B and C mice significantly reduced tumor weight in MC2-R positive tumors in a dose dependent manner (P = 0.03), while no significant difference in tumor mass was observed in MC2-R negative tumors. PCNA and TUNEL staining, together with morphological characterization, demonstrated that these in vivo effects were due to reduced proliferation, while apoptosis and cellular hypertrophy within the tumor remained unchanged.
  
  
  CONCLUSIONS
  MC2-R expression is associated with a less aggressive adrenal tumor phenotype and anti-proliferative effects can be amplified through stimulation with physiological doses of ACTH.
authors.affiliation: Medizinische Klinik-Innenstadt, Ludwig Maximilians University, Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Zwermann
authors.forename: Dominik M
authors.initials: DM
authors.lastname: Schulte
authors.forename: Martin
authors.initials: M
authors.lastname: Reincke
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000308:Adrenocortical Hyperfunction / Q000139:chemically induced; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003345:Corticosterone / Q000097:blood; D003366:Cosyntropin / Q000097:blood / Q000494:pharmacology*; D003692:Delayed-Action Preparations; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D009929:Organ Size; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D003692:Delayed-Action Preparations; D018809:Proliferating Cell Nuclear Antigen; D044103:Receptor, Melanocortin, Type 2; D003366:Cosyntropin; D012313:RNA; D003345:Corticosterone