Somatostatin activates Ras and ERK1/2 via a G protein βγ-subunit-initiated pathway in thyroid cells

Abstract

Somatostatin (SST) is one of the main regulators of thyroid function. It acts by binding to its receptors, which lead to the dissociation of G proteins into Gαi and Gβγ subunits. However, much less is known about the function of Gβγ in thyroid cells. Here, we studied the role of SST and Gβγ dimers released upon SST stimulation on the Ras-ERK1/2 pathway in FTRL-5 thyroid cells. We demonstrate that SST activates Ras through Gi proteins, since SST-induced Ras activation is inhibited by pertussis toxin. Moreover, the specific sequestration of Gβγ dimers decreases Ras-GTP and phosphorylated ERK1/2 levels, and overexpression of Gβγ increases ERK1/2 phosphorylation induced by SST, indicating that Gβγ dimers released after SST treatment mediate activation of Ras and ERK1/2. On the other hand, SST treatment does not modify the expression of the thyroid differentiation marker sodium/iodide symporter (NIS) through ERK1/2 activation. However, SST increases AKT activation and the inhibition of the Src/PI3K/AKT pathway increases NIS levels in SST-treated cells. Thus, we conclude that, in thyroid cells, signalling from SST receptors to ERK1/2 involves a Gβγ-mediated signal acting on a Ras-dependent pathway. Moreover, we demonstrate that SST might regulates NIS expression through a Src/PI3K/AKT-dependent mechanism, but not through ERK1/2 signalling, showing the main role of this hormone in thyroid function.

Evaluation of preclinical efficacy of everolimus and pasireotide in thyroid cancer cell lines and xenograft models

“…Downstream signaling through the mTOR and somatostatin signaling pathways is important for physiologic proliferation and function of the normal thyroid gland. [13, 25, 26] These pathways remain essential following malignant transformation of the thyroid epithelium. [8] There is therefore a valid biological rationale to anticipate that therapeutic targeting of these pathways will result in preclinical and ultimately clinical efficacy.…”