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

Shereen Ezzat,Ri Wang,Melania Pintilie,Sylvia L Asa

doi:10.18632/oncotarget.13843

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.

Highlights

Meta-analysis shows that pituitary tumors are common, occurring in almost 20% of the population [1]; they represent about 10 to 15% of surgically resected intracranial tumors [2,3,4]
Pasireotide was significantly more effective than octreotide in reducing colony formation in FGF receptor 4 (FGFR4)-R388 compared to FGFR4-G388 or to control cells (p-value=0.0003 and 0.004, respectively) (Figure 1b)
We determined if somatostatin receptor 5 (SSTR5) signaling is responsible for the differences we identified in FGFR4-R388 cells

Summary

Introduction

Meta-analysis shows that pituitary tumors are common, occurring in almost 20% of the population [1]; they represent about 10 to 15% of surgically resected intracranial tumors [2,3,4]. The mechanisms underlying the development of sporadic pituitary tumors that rarely involve mutations of classical oncogenes or tumor suppressor genes remain to be clarified [2, 3]. Germline genetic abnormalities associated with pituitary tumor pathogenesis include inactivating mutations of menin in patients with Multiple Endocrine Neoplasia type 1 [5, 6], loss-of-function mutations of the aryl hydrocarbon receptor-interacting protein (AIP) tumor suppressor gene in patients with familial isolated pituitary adenomas [7], and inactivating mutations the Protein kinase A type I regulatory subunit PRKAR1A [8] in patients with Carney complex, these alterations have not been shown to mediate pituitary neoplastic growth in the more common sporadic neoplasms.

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Results

Conclusion