OR26-4 Mitochondrial Respiratory Functions Uncouple Prolifeative Signaling from Hormone Secretion in Response to Somatostatin Analogs

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR26-Pituitary Tumorigenesis: Advances in Mechanism & Treatment
Translational
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:00 PM
Room 130 (Moscone Center)
Toru Tateno*1, Tae Tateno1, Lei Zheng2, Sylvia L. Asa2 and Shereen Z Ezzat1
1Ontario Cancer Institute, Toronto, ON, Canada, 2University Health Network, Toronto, ON, Canada
Backgrounds: Fibroblast growth factor receptor 4 (FGFR4) is a member of a family of transmembrane receptors with tyrosine kinase activity implicated in pituitary tumorigenesis. A single nucleotide polymorphism (SNP) at codon 388 of FGFR4 (Gly388Arg), which encodes an amino acid in the transmembrane part of the FGFR4 gene, was reported to be associated with increased risk of cancer progression. We reported that this SNP can change cell proliferation through STAT3 serine translocation and hormone production through tyrosyl phosphorylation of STAT3 in GH-producing pituitary cells. Here, we examined the differential properties of somatostatin analogs, octreotide and pasireotide in GH-producing cells of the two FGFR4 isotypes.

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.

Tateno T et. al. PloS Genetics 2011.

Nothing to Disclose: TT, TT, LZ, SLA, SZE

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Canadian Institutes of Health Research