Targeting prosurvival BCL2 signaling through Akt blockade sensitizes castration-resistant prostate cancer cells to enzalutamide.

Autor: Pilling AB; Department of Internal Medicine, Division of Hematology/Oncology, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, Michigan., Hwang C; Department of Internal Medicine, Division of Hematology/Oncology, Henry Ford Health System, Henry Ford Cancer Institute, Detroit, Michigan.
Jazyk: angličtina
Zdroj: The Prostate [Prostate] 2019 Aug; Vol. 79 (11), pp. 1347-1359. Date of Electronic Publication: 2019 Jun 22.
DOI: 10.1002/pros.23843
Abstrakt: Background: Prostate cancer that recurs after initial treatment inevitably progresses to castration-resistant prostate cancer (CRPC), the lethal stage of the disease. Despite improvements in outcomes from next generation androgen receptor (AR)-axis inhibitors, CRPC remains incurable. Therapeutic strategies to target AR antagonist resistance are urgently needed to improve outcomes for men with this lethal form of prostate cancer.
Methods: Apoptosis and BCL2 family signaling were characterized in cell line models of CRPC. Quantitative real-time polymerase chain reaction and Western blot analysis were used to determine BCL2 expression levels. Drug sensitivity was determined by proliferation, survival and apoptosis analysis. Protein-protein interactions were evaluated by coimmunoprecipitation followed by Western blot detection.
Results: In the present study, we identify antiapoptotic BCL2 protein signaling as a mechanism of resistance to AR antagonist enzalutamide. In CRPC cell line models, we found that BCL-xL and MCL-1 proteins block apoptosis through binding and sequestering proapoptotic proteins BIM and BAX, resulting in cell survival in response to enzalutamide. Treatment with BH3-mimetics targeting BCL-xL or MCL-1 disrupts these interactions and activates apoptosis, sensitizing CRPC cells to enzalutamide. Importantly, we demonstrate that PI3K/Akt signaling is activated in response to enzalutamide and mediates apoptosis evasion through inactivation of BAD, a BH3-only protein that activates proapoptotic signlaing through inhbition of BCL-xL. Inhibition of Akt activates BAD, resulting in increased apoptosis and sensitivity to enzalutamide, demonstrating an alternative therapeutic strategy to target drug resistance.
Conclusions: These results demonstrate that CRPC cells employ multiple mechanisms to mediate apoptosis evasion through BCL2 signaling, suggesting this pathway is critical for survival. This study provides a strong preclinical rationale for developing therapeutic strategies to target antiapoptotic BCL2 signaling in combination with AR antagonists to improve treatment options for patients with advanced prostate cancer.
(© 2019 The Authors. The Prostate Published by Wiley Periodicals, Inc.)
Databáze: MEDLINE
Externí odkaz: