Octreotide (OCT) is used to inhibit hormone secretion and growth in somatotroph tumors, although a significant proportion of patients develop resistance to the drug. OCT has also been tested in nonfunctional (NF) tumors, but with limited efficacy, results that have been linked to impaired SSTR2 levels and signaling. Here, researchers investigated whether TGF-β1 could enhance the inhibitory effects of OCT in both functional and nonfunctional somatotroph tumor cells. The effects of OCT on hormone secretion and proliferation were analyzed in wild-type (WT), SSTR2-overexpressing secreting GH3, and quiescent somatotroph tumor cells in the presence of TGF-β1. The study demonstrated that both the presence of TGF-β1 and SSTR2 overexpression enhanced the inhibitory effects of OCT on GH and PRL secretion and proliferation. OCT/TGF-β1 treatment induced downregulation of pERK1/2 and pAkt, upregulation of pSmad3, and inhibition of cyclin D1. In vivo experiments showed that in the presence of TGF-β1, OCT inhibited tumor volume growth, reduced cell proliferation, and increased tumor necrosis. These results indicate that SSTR2 levels and stimulation of the TGF-β1/TGFβR/Smad2/3 pathway are crucial for enhancing the antiproliferative and antisecretory effects of OCT.
After observing that TGF-β1 enhanced the antiproliferative effects of OCT, the researchers investigated whether overexpressing SSTR2 in somatotroph tumor cells could optimize this effect. As shown in Figures 1k and 1l, SSTR2-overexpressing GH3 cells showed a significant 34% reduction in proliferation compared with controls transfected with an empty plasmid (pN1-EGFP), suggesting an intrinsic role for SSTR2 as a tumor suppressor. Furthermore, cells treated with OCT combined with TGF-β1 exhibited an additional effect, with a 47% reduction in BrdU uptake compared with untreated SSTR2-overexpressing cells.
Figure 1. Quantification of SSTR2-overexpressing GH3 cell (GH3SSTR2) BrdU uptake after 24-h treatment with OCT, TGF-β1, or the combination of both factors. (Picech F, et al., 2021)