Session: OR26-Pituitary Tumorigenesis: Advances in Mechanism & Treatment
Room 130 (Moscone Center)
Methods and Results: GH4 cells which express growth hormone (GH) and prolactin (PRL) were stably transfected with constructs encoding full length human FGFR4 Gly388 (G388) cDNA or Arg388 (R388) cDNA. The levels of GH and PRL production, secretion, and phosphorylation of STAT3 tyrosine and serine, were examined following somatostatin analog treatment. Cellular mitochondrial functions including basal respiration, ATP turnover, proton leak, and maximal respiration were examined by an XF Extracellular Flux Analyzer with Oligomycin, FCCP, Antimycin A, and Rotenone. Consistent with their enhanced growth properties FGFR4-R388 cells showed higher basal and maximal oxygen consumption rate (OCR) than FGFR4-WT cells. Octreotide and pasireotide decreased OCR resulting in growth inhbition. However, pasireotide was more effective at reducing maximal OCR in FGFR4-R388 cells compared to octreotide. These latter effects were recapitulated by introducing constitutively active serine STAT3 mutants demonstrating octreotide resistance. In contrast, FGFR4-R388 cells which produced more GH responded hormonally to pasireotide but not octreotide. The latter effect was ascribed to the ability of pasireotide, but not octreotide, to re-express pY-STAT3 to inhibit somatotroph GH gene expression.
Conclusions: Our data suggest that the FGFR4 SNP can increase mitochondrial oxygen consumption rate leading to increased cell proliferation representing a target for somatostatin analog growth inhibition. Additionally, pasireotide appears to be more effective at reducing GH production in somatotrophs expressing the variant FGFR4-R388 allele through STAT3 tyrosyl phosphorylation. The results underscore the distinct pathways engaged in and targeted by different somatostatin analogs in neoplastic growth and hormone production with therapeutic implications to the use of these agents.
Nothing to Disclose: TT, TT, LZ, SLA, SZE
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