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Low Levels of Raf Kinase Inhibitory Protein in Growth Hormone-Secreting Pituitary Adenomas Correlate with Poor Response to Octreotide Treatment

Research Institute for Internal Medicine (S.L.F.), University of Oslo, N-0027 Oslo, Norway; Hormone Laboratory, Aker University Hospital (F.L., T.L., J.P.B.), University of Oslo, N-0027 Oslo, Norway; and Section of Endocrinology (S.L.F., J.B.), and Departments of Radiology (J.K.H.) and Neurosurgery (J.R.-P.), Rikshospitalet Medical Centre, N-0027 Oslo, Norway

Address all correspondence and requests for reprints to: Stine Lyngvi Fougner, Research Institute for Internal Medicine, Section of Endocrinology, Rikshospitalet Medical Centre, N-0027 Oslo, Norway. E-mail: s.l.fougner{at}medisin.uio.no.

Context: Excessive GH production by pituitary tumors causes acromegaly. Medical treatment of acromegaly with somatostatin analogs (SMSs), like octreotide, is well established, but the clinical effect is variable. One mechanism for octreotide effect is inhibition of the MAPK signaling pathway after binding to the G protein-coupled somatostatin receptor. Nonphosphorylated Raf kinase inhibitory protein (RKIP) binds to and inhibits Raf1 kinase, and thereby attenuates MAPK signaling, whereas phosphorylated RKIP inhibits G protein receptor internalization and degradation due to inhibition of G protein receptor kinase 2.

Objective: Our objective was to study RKIP levels in pituitary somatotroph adenomas, and relate them to clinical characteristics and response to octreotide treatment in patients with acromegaly.

Patients and Methods: RKIP level was analyzed by Western blot of proteins extracted from somatotroph tumors frozen a short time after surgery in 51 patients with active acromegaly. An acute somatostatin test was performed in 46 of the patients, and in 21 the IGF-I level before and 6 months after SMS treatment was available.

Results: The adenoma RKIP level correlated significantly to both the acute and the long-term octreotide responses on serum levels of GH and IGF-I, respectively. In multiple regression analyses, the RKIP level was a significant determinant for both the GH reduction in the acute test and the IGF-I reduction after approximately 6 months.

Conclusion: The RKIP level in somatotroph adenomas seems to be important for the clinical effect of SMS treatment, in which low levels of RKIP correlate to poor clinical response to SMSs.