Oncotarget

Research Papers:

FGFR4 polymorphic alleles modulate mitochondrial respiration: A novel target for somatostatin analog action in pituitary tumors

Shereen Ezzat _, Ri Wang, Melania Pintilie and Sylvia L. Asa

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Oncotarget. 2017; 8:3481-3494. https://doi.org/10.18632/oncotarget.13843

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Abstract

Shereen Ezzat1, Ri Wang2, Melania Pintilie3, Sylvia L. Asa4

1Department of Medicine, The Endocrine Oncology Site Group, Princes Margaret Cancer Centre, and the Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

2Department of Statistics, University of Waterloo, Toronto, Canada

3Department of Biostatistics, University of Toronto, Toronto, Canada

4Department of Pathology, University Health Network, Toronto, Canada

Correspondence to:

Shereen Ezzat, email: [email protected]

Keywords: FGFR4, FGFR4-R388, mitochondrial functions, somatostatin analogs, pituitary tumors

Received: October 07, 2016     Accepted: November 16, 2016     Published: December 09, 2016

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.


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