title: Differential ligand-mediated pituitary somatostatin receptor subtype signaling: implications for corticotroph tumor therapy.
abstract: OBJECTIVE
  Pituitary targeted pharmacotherapy for Cushing's disease is challenging and ineffective. Unlike octreotide and lanreotide, the multisomatostatin receptor (SST) analog pasireotide that exhibits SST5 greater than SST2 binding affinity offers potential for treating Cushing's disease. Because corticotroph cells express SST5 more abundantly than SST2, pasireotide likely exerts superior corticotroph action mainly through SST5. However, there is no direct evidence for this assumption, and moreover, the ligand effect on corticotroph SST2 is not known.
  
  
  RESULTS
  We used AtT20 mouse pituitary corticotroph tumor cells stably overexpressing SST2 or SST5 and TtT/GF mouse pituitary folliculostellate cells stably or transiently expressing SST receptors to examine ligand-receptor activation by SST2- and SST5-selective agonists. We show that pasireotide was more potent than either octreotide or somatostatin-14 in mouse corticotroph cells. Pasireotide potency is not affected by SST2 abundance, SST2 antagonist treatment, or octreotide cotreatment in SST2-overexpressing cells. Pasireotide also does not induce SST2 internalization and attenuates octreotide or SRIF14-induced SST2 internalization only at superphysiological dose ranges. In contrast, octreotide attenuates pasireotide potency in SST5-overexpressing cells. Moreover, short exposure to pasireotide causes prolonged inhibition of forskolin or CRH-induced cAMP accumulation, in contrast to somatostatin-14- and SST2-selective agonists that induced postwithdrawal cAMP rebound. Long-term pasireotide signaling effects are enhanced by SST5 overexpression.
  
  
  CONCLUSIONS
  The results indicate that SST5 determines short- and long-term enhanced pasireotide action in corticotroph cells, whereas the ligand action on SST2 is negligible.
authors.affiliation: Department of Medicine, Pituitary Center, Cedars SinaiMedical Center, Los Angeles, California 90048, USA.
authors.forename: Anat
authors.initials: A
authors.lastname: Ben-Shlomo
authors.forename: Herbert
authors.initials: H
authors.lastname: Schmid
authors.forename: Kolja
authors.initials: K
authors.lastname: Wawrowsky
authors.forename: Oxana
authors.initials: O
authors.lastname: Pichurin
authors.forename: Erika
authors.initials: E
authors.lastname: Hubina
authors.forename: Vera
authors.initials: V
authors.lastname: Chesnokova
authors.forename: Ning-Ai
authors.initials: NA
authors.lastname: Liu
authors.forename: Michael
authors.initials: M
authors.lastname: Culler
authors.forename: Shlomo
authors.initials: S
authors.lastname: Melmed
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D015282:Octreotide / Q000627:therapeutic use; D047748:Pituitary ACTH Hypersecretion / Q000188:drug therapy; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000145:classification / Q000235:genetics / Q000502:physiology*; D013004:Somatostatin / Q000627:therapeutic use; D014162:Transfection
chemical_list: D008024:Ligands; D017481:Receptors, Somatostatin; D013004:Somatostatin; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D015282:Octreotide