Author ORCID Identifier
Document Type
Article
Publication Date
5-26-2023
Abstract
Abiraterone acetate has been clinically approved for the treatment of patients with advanced‐stage prostate cancer. It reduces testosterone production by blocking the enzyme cytochrome P450 17 alpha‐hydroxylase. Despite improved survival outcomes with abiraterone, almost all patients develop therapeutic resistance and disease recurrence, progressing to a more aggressive and lethal phenotype. Bioinformatics analyses predicted activation of canonical Wnt/β‐catenin and involvement of stem cell plasticity in abiraterone‐resistant prostate cancer. Increased expression of androgen receptor (AR) and β‐catenin and their crosstalk causes activation of AR target genes and regulatory networks for which overcoming acquired resistance remains a major challenge. Here we show that co‐treatment with abiraterone and ICG001, a β‐catenin inhibitor, overcomes therapeutic resistance and significantly inhibited markers of stem cell and cellular proliferation in abiraterone‐resistant prostate cancer cells. Importantly, this combined treatment abrogated the association between AR and β‐catenin; diminished SOX9 expression from the complex more prominently in abiraterone‐resistant cells. In addition, combined treatment inhibited tumor growth in an in vivo abiraterone‐resistant xenograft model, blocked stemness, migration, invasion, and colony formation ability of cancer cells. This study opens new therapeutic opportunity for advanced‐stage castration‐resistant prostate cancer patients.
Keywords
androgen deprivation therapy, androgen receptor, cancer stem cells, castration resistant prostate cancer, an signaling pathways
Publication Title
Molecular Carcinogenesis
Rights
© 2023 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Recommended Citation
Atawia IM, Kushwaha PP, Verma S,et al. Inhibition of Wnt/β‐catenin pathway overcomestherapeutic resistance to abiraterone in castration‐resistantprostate cancer. Molecular Carcinogenesis. 2023;62:1312‐1324. doi:10.1002/mc.23565