Journal article
Inhibition of autophagy significantly increases the antitumor effect of Abiraterone in prostate cancer.
- Mortezavi A Laboratory for Tissue Engineering and Stem Cell Therapy, Department of Urology, University Hospital Zürich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland.
- Salemi S Laboratory for Tissue Engineering and Stem Cell Therapy, Department of Urology, University Hospital Zürich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland.
- Kranzbühler B Laboratory for Tissue Engineering and Stem Cell Therapy, Department of Urology, University Hospital Zürich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland.
- Gross O Laboratory for Tissue Engineering and Stem Cell Therapy, Department of Urology, University Hospital Zürich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland.
- Sulser T Laboratory for Tissue Engineering and Stem Cell Therapy, Department of Urology, University Hospital Zürich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland.
- Simon HU Institute of Pharmacology, University of Bern, Inselspital, INO-F, 3010, Bern, Switzerland.
- Eberli D Laboratory for Tissue Engineering and Stem Cell Therapy, Department of Urology, University Hospital Zürich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland. daniel.eberli@usz.ch.
- 2018-06-29
Published in:
- World journal of urology. - 2019
Abiraterone
Autophagy
PCa
Abiraterone Acetate
Adenine
Antineoplastic Agents
Apoptosis
Autophagy
Autophagy-Related Protein 5
Cell Death
Cell Line, Tumor
Cell Survival
Chloroquine
Drug Resistance, Neoplasm
Humans
Male
Prostatic Neoplasms, Castration-Resistant
English
PURPOSE
Abiraterone acetate (AA) plus prednisone is an approved treatment of advanced prostate cancer (PCa). Autophagy is linked to drug resistance in numerous types of cancers. We hypothesized, that upregulation of autophagy is one of the mechanisms by which PCa cells survive AA anti-tumor treatment and therefore evaluated the potential effect of a combination with autophagy inhibition.
METHODS
Human PCa LNCaP cell lines were cultured in steroid-free medium and treated with AA. Autophagy was inhibited by 3-methyladenine, chloroquine and ATG5 siRNA knock-down. Cell viability and apoptosis was assessed by flow cytometry and fluorescence microscopy, and autophagy was monitored by immunohistochemistry, AUTOdot and Western blotting.
RESULTS
Western blot revealed upregulation of ATG5 and LC3 II with a reduction of p62 protein expression in AA-treated cells, indicating upregulation of autophagy. These data were supported by results obtained with immunocytochemistry and AUTOdot assays. Using flow cytometry, we showed that combining AA with autophagy inhibition significantly impaired cell viability (1.3-1.6-fold, p < 0.001) and increased apoptosis (1.4-1.5-fold, p < 0.001) compared to AA treatment alone.
CONCLUSIONS
AA activates autophagy as a cytoprotective mechanism in LNCaP prostate cancer cells and targeting of autophagy enhances the antitumor effect of the compound.
Abiraterone acetate (AA) plus prednisone is an approved treatment of advanced prostate cancer (PCa). Autophagy is linked to drug resistance in numerous types of cancers. We hypothesized, that upregulation of autophagy is one of the mechanisms by which PCa cells survive AA anti-tumor treatment and therefore evaluated the potential effect of a combination with autophagy inhibition.
METHODS
Human PCa LNCaP cell lines were cultured in steroid-free medium and treated with AA. Autophagy was inhibited by 3-methyladenine, chloroquine and ATG5 siRNA knock-down. Cell viability and apoptosis was assessed by flow cytometry and fluorescence microscopy, and autophagy was monitored by immunohistochemistry, AUTOdot and Western blotting.
RESULTS
Western blot revealed upregulation of ATG5 and LC3 II with a reduction of p62 protein expression in AA-treated cells, indicating upregulation of autophagy. These data were supported by results obtained with immunocytochemistry and AUTOdot assays. Using flow cytometry, we showed that combining AA with autophagy inhibition significantly impaired cell viability (1.3-1.6-fold, p < 0.001) and increased apoptosis (1.4-1.5-fold, p < 0.001) compared to AA treatment alone.
CONCLUSIONS
AA activates autophagy as a cytoprotective mechanism in LNCaP prostate cancer cells and targeting of autophagy enhances the antitumor effect of the compound.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1007/s00345-018-2385-5
- PMID 29951789
- Persistent URL
- https://folia.unifr.ch/global/documents/140591
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