Inhibition of Notch signaling attenuates pituitary adenoma growth in Nude mice

ZUBELDÍA-BRENNER, L.; DE WINNE, C.; PERRONE, S.; RODRÍGUEZ-SEGUÍ, S.A.; WILLEMS, C.; ORNSTEIN, A.M.; LACAU-MENGIDO, I.; VANKELECOM, H.; CAROLINA, C.; BECU-VILLALOBOS, D.

ENDOCRINE - RELATED CANCER

BIOSCIENTIFICA LTD

Lugar: Bristol; Año: 2019

1351-0088

Preclinicaland clinical studies support that Notch signaling may play animportant oncogenic role in cancer, but there is scarce informationfor pituitary tumors. We therefore undertook a functional study toevaluate Notch participation in pituitary adenoma growth. Tumorsgenerated in Nude mice by subcutaneous GH3 somatolactotrope cellinjection were treated invivowith DAPT, a γ-secretase inhibitor, thus inactivating Notchsignaling. This treatment led to pituitary tumor reduction, lowerprolactin and GH tumor content, and a decrease in angiogenesis. Furthermore, insilicotranscriptomic and epigenomic analyses uncovered several tumorsuppressor genes related to Notch signaling in pituitary tissue,namely Btg2,Nr4a1, Men1, Zfp36, andCnot1.Gene evaluation suggested that Btg2,Nr4a1 andCnot1may be possible players in GH3 xenograft growth. Btg2mRNA expression was lower in GH3 tumors compared to the parentalline, and DAPT increased its expression levels in the tumor inparallel with the inhibition of its volume. Cnot1mRNA levels were also increased in the pituitary xenografts by DAPTtreatment. And the Nr4a1gene was lower in tumors compared to the parental line, though notmodified by DAPT. Finally, because DAPT invivomay be also acting on tumor microenvironment, we determined thedirect effect of DAPT on GH3 cells invitro.We found that DAPT decreases the proliferative, secretory andmigration potential of GH3 cells. These results position selectiveinterruption of Notch signaling as a potential therapeutic tool inadjuvant treatments for aggressive or resistant pituitary tumors.p { margin-bottom: 0in; direction: ltr; color: rgb(0, 0, 0); line-height: 150%; text-align: justify; }p.western { font-family: "Times New Roman", serif; font-size: 11pt; }p.cjk { font-family: "Times New Roman", serif; font-size: 11pt; }p.ctl { font-family: "Times New Roman", serif; font-size: 29pt; }a:link { color: rgb(0, 0, 255); }