Androgen deprivation and androgen receptor competition by bicalutamide induce autophagy of hormone-resistant prostate cancer cells and confer resistance to apoptosis.
Details
Serval ID
serval:BIB_FEF3D64AE478
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Androgen deprivation and androgen receptor competition by bicalutamide induce autophagy of hormone-resistant prostate cancer cells and confer resistance to apoptosis.
Journal
The Prostate
ISSN
1097-0045 (Electronic)
ISSN-L
0270-4137
Publication state
Published
Issued date
07/2013
Peer-reviewed
Oui
Volume
73
Number
10
Pages
1090-1102
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Treatment of advanced prostate cancer (PCa) relies on pharmacological or surgical androgen deprivation. However, it is only temporarily efficient. After a few months or years, the tumor relapses despite the absence of androgenic stimulation: a state referred to as hormone-refractory prostate cancer (HRPCa). Although autophagy confers chemoresistance in some cancers, its role in the development of HRPCa remains unknown.
Autophagic flux was assayed by GFP-LC3 clustering, by LC3-I to LC3-II conversion and transmission electron microscopy. Cell death was detected by sub-G1 quantification and concomitant measurement of transmembrane mitochondrial potential and plasma membrane permeabilization. Inhibition of autophagy was achieved by siRNAs and pharmacological inhibitors.
Androgen deprivation or treatment with the anti-androgen bicalutamide promoted autophagy in HRPCa-derived LNCaP cells. This effect was dramatically reduced after depletion of Atg5 and Beclin-1, two canonical autophagy genes, and was associated with an inhibition of the androgen-induced mTOR pathway. The depletion of Atg5 and Beclin-1 significantly increased the level of cell death induced by androgen deprivation or bicalutamide. Finally, the safe anti-malarial drug chloroquine, an inhibitor of autophagy, dramatically increased cell death after androgen deprivation or bicalutamide treatment.
Taken together, our data suggest that autophagy is a protective mechanism against androgen deprivation in HRPCa cells and that chloroquine could restore hormone dependence. This set of data could lead to the development of new therapeutic strategy against HRPCa.
Autophagic flux was assayed by GFP-LC3 clustering, by LC3-I to LC3-II conversion and transmission electron microscopy. Cell death was detected by sub-G1 quantification and concomitant measurement of transmembrane mitochondrial potential and plasma membrane permeabilization. Inhibition of autophagy was achieved by siRNAs and pharmacological inhibitors.
Androgen deprivation or treatment with the anti-androgen bicalutamide promoted autophagy in HRPCa-derived LNCaP cells. This effect was dramatically reduced after depletion of Atg5 and Beclin-1, two canonical autophagy genes, and was associated with an inhibition of the androgen-induced mTOR pathway. The depletion of Atg5 and Beclin-1 significantly increased the level of cell death induced by androgen deprivation or bicalutamide. Finally, the safe anti-malarial drug chloroquine, an inhibitor of autophagy, dramatically increased cell death after androgen deprivation or bicalutamide treatment.
Taken together, our data suggest that autophagy is a protective mechanism against androgen deprivation in HRPCa cells and that chloroquine could restore hormone dependence. This set of data could lead to the development of new therapeutic strategy against HRPCa.
Keywords
Androgen Antagonists/pharmacology, Androgen Antagonists/therapeutic use, Anilides/pharmacology, Anilides/therapeutic use, Antineoplastic Agents/pharmacology, Antineoplastic Agents/therapeutic use, Apoptosis/drug effects, Autophagy/drug effects, Cell Line, Tumor, Chloroquine/pharmacology, Humans, Male, Nitriles/pharmacology, Nitriles/therapeutic use, Prostate/drug effects, Prostate/metabolism, Prostatic Neoplasms/drug therapy, Prostatic Neoplasms/metabolism, Receptors, Androgen/metabolism, TOR Serine-Threonine Kinases/metabolism, Tosyl Compounds/pharmacology, Tosyl Compounds/therapeutic use
Pubmed
Web of science
Create date
27/01/2023 19:02
Last modification date
28/01/2023 6:48