THERAPEUTIC POTENTIAL OF TARGETING THE FLNA-REGULATED WEE1 KINASE PATHWAY IN ADRENOCORTICAL CARCINOMAS.
type: CreativeWork
description: Adrenocortical carcinomas (ACC) are highly aggressive tumors with very limited treatment options. Alterations in cell cycle-related genes have been identified as key ACC drivers, and they are largely present in the most aggressive tumor subtypes. Compared to benign adenomas (ACA), the cytoskeletal protein filamin A (FLNA) is poorly expressed in ACC. Of note, its presence, even at low levels, is associated to a less aggressive tumor behaviour, potentially due to its role in negatively regulating the insulin-like growth factor 1 receptor (IGF1R) signalling. Upregulation of Wee1 nuclear kinase, a key regulator of G2/M cell cycle checkpoint, was shown in mouse neural progenitor cells lacking FLNA, and it has been reported in several cancers. The first part of this PhD thesis is focused 1) on the analysis of Wee1 expression in ACC and its regulation by FLNA, 2) on the effects of the specific Wee1 inhibitor AZD1775, 3) and lastly on the impact of FLNA on its efficacy in three different ACC cell lines (H295R, MUC-1, and TVBF-7) and in patient-derived primary cultured ACC cells. Analysis of FLNA and Wee1 proteins revealed elevated Wee1 and reduced FLNA in ACC compared to normal adrenal gland (NAG). FLNA knockdown increased Wee1 protein in H295R, MUC-1, and in primary ACC cells. Higher p-CDK1 and cyclin B1 were shown in FLNA-silenced MUC-1, while decreased Wee1, p-CDK1 and cyclin B1 resulted after FLNA overexpression. Notably, Wee1 depletion was reverted by lactacystin treatment, and FLNA transfection increased Wee1 phosphorylation at Ser123 residue, suggesting FLNA role in targeting Wee1 for proteasomal degradation. AZD1775 dose-dependently reduced proliferation and viability in ACC cell lines and primary cultures, and it triggered MUC-1 cells death. Similar effects were induced by Wee1 silencing. FLNA depletion augmented AZD1775 efficacy in reducing proliferation and potentiating apoptosis in MUC-1 and primary cells. In conclusion, we demonstrated that FLNA regulates Wee1 …
abstract: Adrenocortical carcinomas (ACC) are highly aggressive tumors with very limited treatment options. Alterations in cell cycle-related genes have been identified as key ACC drivers, and they are largely present in the most aggressive tumor subtypes. Compared to benign adenomas (ACA), the cytoskeletal protein filamin A (FLNA) is poorly expressed in ACC. Of note, its presence, even at low levels, is associated to a less aggressive tumor behaviour, potentially due to its role in negatively regulating the insulin-like growth factor 1 receptor (IGF1R) signalling. Upregulation of Wee1 nuclear kinase, a key regulator of G2/M cell cycle checkpoint, was shown in mouse neural progenitor cells lacking FLNA, and it has been reported in several cancers. The first part of this PhD thesis is focused 1) on the analysis of Wee1 expression in ACC and its regulation by FLNA, 2) on the effects of the specific Wee1 inhibitor AZD1775, 3) and lastly on the impact of FLNA on its efficacy in three different ACC cell lines (H295R, MUC-1, and TVBF-7) and in patient-derived primary cultured ACC cells. Analysis of FLNA and Wee1 proteins revealed elevated Wee1 and reduced FLNA in ACC compared to normal adrenal gland (NAG). FLNA knockdown increased Wee1 protein in H295R, MUC-1, and in primary ACC cells. Higher p-CDK1 and cyclin B1 were shown in FLNA-silenced MUC-1, while decreased Wee1, p-CDK1 and cyclin B1 resulted after FLNA overexpression. Notably, Wee1 depletion was reverted by lactacystin treatment, and FLNA transfection increased Wee1 phosphorylation at Ser123 residue, suggesting FLNA role in targeting Wee1 for proteasomal degradation. AZD1775 dose-dependently reduced proliferation and viability in ACC cell lines and primary cultures, and it triggered MUC-1 cells death. Similar effects were induced by Wee1 silencing. FLNA depletion augmented AZD1775 efficacy in reducing proliferation and potentiating apoptosis in MUC-1 and primary cells. In conclusion, we demonstrated that FLNA regulates Wee1 …
author: ESPOSITO, EMANUELA
language: eng
keywords: filamin A, Wee1, cell cycle, therapeutic target, Settore MEDS-26/A - Scienze tecniche di medicina di laboratorio, Settore MEDS-08/A - Endocrinologia
date published: 2025-01-15
date modified: 2026-07-27T20:19:03Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2434/1128195

PropertyValue
property ID: DOI
value: 10.13130/esposito-emanuela_phd2025-01-15