Inhibition of Wnt/β‐catenin pathway overcomes therapeutic resistance to abiraterone in castration‐resistant prostate cancer

Author:

Atawia Ibrahim M.12,Kushwaha Prem P.13,Verma Shiv13,Lin Spencer4,Shankar Eswar13,Abdel‐Gawad Osama2,Gupta Sanjay13567ORCID

Affiliation:

1. Department of Urology Case Western Reserve University Cleveland Ohio USA

2. Department of Urology Menoufia University Menoufia Egypt

3. University Hospitals Cleveland Medical Center The Urology Institute Cleveland Ohio USA

4. College of Arts and Sciences Case Western Reserve University Cleveland Ohio USA

5. Department of Pharmacology Case Western Reserve University Cleveland Ohio USA

6. Department of Pathology Case Western Reserve University Cleveland Ohio USA

7. Department of Nutrition Case Western Reserve University Cleveland Ohio USA

Abstract

AbstractAbiraterone 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.

Funder

U.S. Department of Defense

Publisher

Wiley

Subject

Cancer Research,Molecular Biology

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