TGF‐β1/Smad2/3 signaling pathway modulates octreotide antisecretory and antiproliferative effects in pituitary somatotroph tumor cells

Abstract

Octreotide (OCT) is used to inhibit hormone secretion and growth in somatotroph tumors, although a significant percentage of patients are resistant. It has also been tested in nonfunctioning (NF) tumors but with poor results, with these outcomes having been associated with SSTR2 levels and impaired signaling. We investigated whether OCT inhibitory effects can be improved by TGF‐β1 in functioning and nonfunctioning somatotroph tumor cells. OCT effects on hormone secretion and proliferation were analyzed in the presence of TGF‐β1 in WT and SSTR2‐overexpressing secreting GH3 and silent somatotroph tumor cells. The mechanism underlying these effects was assessed by studying SSTR and TGFβR signaling pathways mediators. In addition, we analyzed the effects of OCT/TGF‐β1 treatment on tumor growth and cell proliferation in vivo. The inhibitory effects of OCT on GH‐ and PRL‐secretion and proliferation were improved in the presence of TGF‐β1, as well as by SSTR2 overexpression. The OCT/TGF‐β1 treatment induced downregulation of pERK1/2 and pAkt, upregulation of pSmad3, and inhibition of cyclin D1. In vivo experiments showed that OCT in the presence of TGF‐β1 blocked tumor volume growth, decreased cell proliferation, and increased tumor necrosis. These results indicate that SSTR2 levels and the stimulation of TGF‐β1/TGFβR/Smad2/3 pathway are important for strengthening the antiproliferative and antisecretory effects of OCT.

Transcriptome of GH-producing pituitary neuroendocrine tumours and models are significantly affected by somatostatin analogues

“…Incubating pituispheres with cabergoline for 4 h, 24 h, 48 h, and 72 h (except 8 h) we observed ADP Ribosylation Factor GTPase Activating Protein 1 (ARFGAP1) gene downregulation. When incubating pituispheres with cabergoline for 8 h and 24 h, expression alterations of Transforming Growth Factor Beta Receptor 2 (TGFBR2) and Epidermal Growth Factor Receptor Pathway Substrate 8 (EPS8) were noticed, these pathways have been elaborately studied in relation to PitNETs [43][44][45][46][47][48][49][50][51][52]. The significance of cadherins in PitNETs was already made clear in the early 2000s [53,54].…”

Oxidative stress in pituitary neuroendocrine tumors: Affecting the tumor microenvironment and becoming a new target for pituitary neuroendocrine tumor therapy

“…Similar to other tumors, factors such as cell cycle dysregulation, abnormal metabolic pathways, growth factor overexpression, defective signaling pathways, epigenetic silencing of tumor suppressor genes, oncogene overexpression, and an altered microenvironment are the focus of research attention in PitNETs. 10 , 11 , 12 The transformation of normal cells into tumor cells is accompanied by changes in cellular metabolism and mitochondrial function, which means that the internal physiological responses of tumor cells are usually significantly different from the external effects of normal cells. 13 , 14 Moreover, transformed cells can recruit and corrupt other cells to establish the tumor microenvironment (TME).…”