Inhibition of gamma-secretase in Notch1 signaling pathway as a novel treatment for ovarian cancer

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. Most patients are not diagnosed until the cancer is at an advanced stage with poor prognosis. Notch1 signaling pathway plays an oncogenic role in EOC. There have been few studies on enzymatic activity of γ-secretase and the mechanism of how γ-secretase inhibitor works on cancer cell. Here, we show that Jagged1 and NICD were highly expressed in ovarian carcinoma. The expressions of Notch1, Jagged1 and NICD in Notch1 pathway did not correlate with outcome in ovarian cancer. The enzymatic activity of γ-secretase in ovarian cancer cell lines SKOV3, CAOV3 and ES2 is significantly higher than in normal ovarian epithelial cell line T29. DAPT (a γ-secretase inhibitor) reduced the enzymatic activity of γ-secretase, inhibited the proliferation, and increased the apoptosis in ovarian cancer cell lines. Hence, γ-secretase inhibitor may become a highly promising novel therapeutic strategy against ovarian cancer in the field of precision medicine.

Prognostic roles of Notch receptor mRNA expression in human ovarian cancer

“…However, so far, not many specific small molecular inhibitors or other antagonists of the different Notch members have been developed. γ-secretase inhibitor, DAPT was demonstrated to inhibit Notch activation and cell growth in ovarian cancer cells [21]. However, γ-secretase inhibitors are not able to distinguish individual Notch receptors and may cause intestinal toxicity [59] by inhibiting other signaling pathways [60].…”

“…Recently, a number of studies also demonstrated that Notch signaling pathway, especially Notch1 is important for maintaining cancer stem cells in ovarian cancer [18–20]. DAPT, a γ-secretase inhibitor, which reduces gamma-secretase in Notch1 signaling pathway was reported as a highly promising novel therapeutic drug candidate for ovarian cancer patient [21]. LY900009, a first-in-human phase I study of the oral Notch inhibitor was also reported in patients with advanced cancer including ovarian cancer [22].…”

Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

“…A high NOTCH4 mRNA expression level was revealed to be significantly correlated with a favourable overall survival (OS) of EOC patients and thus was regarded as a prognostic factor 16. As the γ‐secretase inhibitors in the Notch signalling pathway, DAPT and MK‐0752 have been reported to be highly promising therapeutic drug targets for treatment of EOC patients 17, 18. Recently, a 10‐gene signature of the Notch signalling pathway, including FZD3 , HES1 , PSEN2 , JAG2 , PPARG , FOS , HEY1 , CDC16 , MFNG and EP300 , has been identified to be associated with a higher risk of recurrence of EOC 19.…”

“…16 As the γ-secretase inhibitors in the Notch signalling pathway, DAPT and MK-0752 have been reported to be highly promising therapeutic drug targets for treatment of EOC patients. 17,18 Recently, a 10-gene signature of the Notch signalling pathway, including FZD3, HES1, PSEN2, JAG2, PPARG, FOS, HEY1, CDC16, MFNG and EP300, has been identified to be associated with a higher risk of recurrence of EOC. 19 Therefore, the Notch signalling pathway has been suggested to have biological significance and important value in the prognosis of EOC.…”

microRNA-1271-5p/TIAM1 suppresses the progression of ovarian cancer through inactivating Notch signaling pathway

“…Thus, to verify whether the biological effect of miR-1271-5p/TIAM1 axis in OC cells is associated with the activity of Notch signaling pathway, we measured the levels of related proteins including Cyclin D1, HES1, Notch and NUMB by western blot. Notch1 is a highly conserved member of Notch family and exerts a vital role in various cancers [ 34 ]. Increased Notch1 expression is correlated with unfavorable prognosis of OC patients [ 35 ].…”