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Inhibition of autophagy significantly increases the antitumor effect of Abiraterone in prostate cancer


Mortezavi, Ashkan; Salemi, Souzan; Kranzbühler, Benedikt; Gross, Oliver; Sulser, Tullio; Simon, Hans-Uwe; Eberli, Daniel (2019). Inhibition of autophagy significantly increases the antitumor effect of Abiraterone in prostate cancer. World Journal of Urology, 37(2):351-358.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Urological Clinic
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Abiraterone, Autophagy, PCa
Date:1 February 2019
Deposited On:02 Aug 2018 15:23
Last Modified:13 Feb 2019 02:01
Publisher:Springer
ISSN:0724-4983
OA Status:Closed
Publisher DOI:https://doi.org/10.1007/s00345-018-2385-5
PubMed ID:29951789

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