title: FGFR4 polymorphic alleles modulate mitochondrial respiration: A novel target for somatostatin analog action in pituitary tumors.
abstract: We reported that a single nucleotide polymorphism (SNP) at codon 388 of the fibroblast growth factor receptor 4 (FGFR4-Gly388Arg) can result in distinct proteins that alter pituitary cell growth and function. Here, we examined the differential properties of the available therapeutic somatostatin analogs, octreotide and pasireotide, in pituitary tumor cells expressing the different FGFR4 isoforms. Consistent with their enhanced growth properties, FGFR4-R388-expressing cells show higher mitochondrial STAT3 serine phosphorylation driving basal and maximal oxygen consumption rate (OCR) than pituitary cells expressing the more common FGFR4-G388 isoform. While both somatostatin analogs reduce the OCR in FGFR4-G388 cells, pasireotide was more effective in decreasing OCR in cells expressing the variant FGFR4-R388 isoform. Down-regulation of somatostatin receptor 5 (SSTR5) abrogated the effect of pasireotide, demonstrating its involvement in mediating this action. The effects on OCR were recapitulated by introducing a constitutively active serine STAT3 but not by a tyrosine-active mutant. Moreover, pharmacologic inhibition demonstrated the role for the phosphatase PP2A in mediating the dephosphorylation of STAT3-S727 by pasireotide. Our data indicate that FGFR4 polymorphic isoforms mediate signaling that yields mitochondrial therapeutic targets of relevance to the actions of different somatostatin analogs.
authors.affiliation: Department of Medicine, The Endocrine Oncology Site Group, Princes Margaret Cancer Centre, and the Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Shereen
authors.initials: S
authors.lastname: Ezzat
authors.affiliation: Department of Statistics, University of Waterloo, Toronto, Canada.
authors.forename: Ri
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, University of Toronto, Toronto, Canada.
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.affiliation: Department of Pathology, University Health Network, Toronto, Canada.
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
mesh_terms: D000483:Alleles; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D015282:Octreotide / Q000494:pharmacology; D010766:Phosphorylation; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D050796:STAT3 Transcription Factor; D013004:Somatostatin; C517782:pasireotide; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D015282:Octreotide
keywords: FGFR4; FGFR4-R388; mitochondrial functions; pituitary tumors; somatostatin analogs