Abstract 4869: Furin and Notch signaling pathway as part of the 2OHOA landscape against glioblastoma

Abstract

Abstract Glioblastoma (GBM) is the most common and aggressive cancer tumor of the central nervous system, with only 12-15 months of patients’ median survival. Melitherapy is a novel therapeutic platform based on the regulation of the membrane’s structure and organization with the consequent modulation of certain cell signals. In this context, 2-hydroxioleic acid (2OHOA, LAM561, INN: idroxioleic acid) has been developed for the treatment of GBM and is currently running a phase IIB/III clinical trial for newly diagnosed GBM patients. 2OHOA modulates the lipid composition and structure of cancer cells, increasing membranes fluidity and altering the activity of membrane-associated proteins, inhibiting the proliferation, inducing ER stress and differentiation, and finally triggering cell death by autophagy. The Notch signaling pathway has been highly related to tumorigenesis and cell survival driving the pathogenesis of GBM. In this work, we studied whether 2OHOA modulates the Notch pathway and its relevance in its mechanism of action (MoA) as an antitumoral drug. For this purpose, the 2OHOA’s effect on different components of the pathway was studied by western-blot, Q-PCR, and confocal microscopy. In addition, Notch receptor processing and NICD formation (final effector) were analyzed by cell fractionation and Notch processing enzymes activity, like furin, was evaluated upon 2OHOA treatment. First, the inhibition of this pathway in GBM cells by 2OHOA was confirmed by (i) lower expression levels of some of its components (Notch1, Notch3, and Jagged) and target genes (Hes1, CD3), (ii) less nuclear presence of NICD and Hes1 after 2OHOA treatment, (iii) accumulation of full-length Notch receptor in the membranes, impairing its processing and the NICD formation. Second, the relevance of Notch pathway in 2OHOA’s MoA was determined by the partial hindering of 2OHOA antiproliferative effect by Hes1 overexpression. Moreover, the reduction of Hes1 expression induced by the drug in different GBM cells correlated positively with their sensitivity to 2OHOA. Finally, 2OHOA downregulated furin-like proteases activity by physical association, an enzyme responsible for the Notch processing first step. All together reveals that the inhibition of Notch pathway by 2OHOA plays a role in its antitumoral effect, and this event is unleashed by the direct furin enzyme inhibition, identifying it as a novel target for this drug in the GBM and other pathologies treatment. Citation Format: Raquel Rodríguez-Lorca, Roberto Beteta-Göbel, Ramón Román, Manuel Torres, Victoria Llado, Pablo V. Escribá, Paula Fernández-García. Furin and Notch signaling pathway as part of the 2OHOA landscape against glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4869.