Convergence of Wnt and Notch signaling controls ovarian cancer cell survival

Abstract

In the last 40 years ovarian cancer mortality rates have slightly declined and,consequently, it continues to be the fifth cause of cancer death in women. In thepresent study, we showed that β‐catenin signaling is involved in the functions ofovarian cancer cells and interacts with the Notch system. Wnt and Notch systemsshowed to be prosurvival for ovarian cancer cells and their inhibition impaired cellproliferation and migration. We also demonstrated that the inhibition of β‐catenin bymeans of two molecules, XAV939 and ICG‐001, decreased the proliferation of theIGROV1 and SKOV3 ovarian cancer cell lines and that ICG‐001 increased thepercentage of IGROV1 cells undergoing apoptosis. The simultaneous inhibition ofβ‐catenin and Notch signaling, by using the DAPT inhibitor, decreased ovarian cancercell proliferation to the same extent as targeting only the Wnt/β‐catenin pathway. Asimilar effect was observed in IGROV1 cell migration with ICG‐001 and DAPT.ICG‐001 increased the Notch target genes Hes‐1 and Hey‐1 and increased Jagged1expression. However, no changes were observed in Dll4 or Notch 1 and 4expressions. Our results suggest that Notch and β‐catenin signaling co‐operate inovarian cancer to ensure the proliferation and migration of cells and that this couldbe achieved, at least partly, by the upregulation of Notch Jagged1 ligand in theabsence of Wnt signaling. We showed that the Wnt pathway crosstalks with Notch inovarian cancer cell functions, which may have implications in ovarian cancertherapeutics.