TGFb1/Smad2/3 signaling pathway modulates octreotide antisecretory and antiproliferative effects in pituitary somatotroph tumor cells

PICECH, F; SOSA L DEL V.; PEREZ P; CECENARO L; OMS SR; COCCA H; DE BATISTA J; GUTIERREZ, S.; MUKDSI, J. H.; TORRES, A I; PETITI J P

JOURNAL OF CELLULAR PHYSIOLOGY

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2021

0021-9541

Octreotide (OCT) is used to inhibit hormone secretion and growth in somatotrophtumors, although a significant percentage of patients are resistant. It has also beentested in nonfunctioning (NF) tumors but with poor results, with these outcomeshaving been associated with SSTR2 levels and impaired signaling. We investigatedwhether OCT inhibitory effects can be improved by TGF‐β1 in functioning andnonfunctioning somatotroph tumor cells. OCT effects on hormone secretion andproliferation were analyzed in the presence of TGF‐β1 in WT and SSTR2‐overexpressing secreting GH3 and silent somatotroph tumor cells. The mechanismunderlying these effects was assessed by studying SSTR and TGFβR signalingpathways mediators. In addition, we analyzed the effects of OCT/TGF‐β1 treatmenton tumor growth and cell proliferation in vivo. The inhibitory effects of OCT onGH‐ 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 down-regulation of pERK1/2 and pAkt, upregulation of pSmad3, and inhibition of cyclinD1. In vivo experiments showed that OCT in the presence of TGF‐β1 blocked tumorvolume growth, decreased cell proliferation, and increased tumor necrosis. Theseresults indicate that SSTR2 levels and the stimulation of TGF‐β1/TGFβR/Smad2/3pathway are important for strengthening the antiproliferative and antisecretoryeffects of OCT.