PLCɛ maintains the functionality of AR signaling in prostate cancer via an autophagy-dependent mechanism

Androgen receptor (AR) signaling is a major driver of prostate cancer (CaP). Although most therapies targeting AR are initially effective in CaP patients, drug resistance is inevitable, mainly because of the inappropriate re-activation of AR pathway. However, the underlying mechanisms remain largely...

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Bibliographic Details
Published in:Cell death & disease 2020-09, Vol.11 (8), p.716, Article 716
Main Authors: Quan, Zhen, Li, Ting, Xia, Yang, Liu, Jiayu, Du, Zhongbo, Luo, Chunli, He, Yunfeng, Wu, Xiaohou
Format: Article
Language:English
Subjects:
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82/51
96/1
96/109
96/31
96/35
96/63
96/95
Adult
Aged
Androgen receptors
Antibodies
Apoptosis - drug effects
Autophagy
Autophagy - drug effects
Autophagy - physiology
Biochemistry
Biomedical and Life Sciences
Cell adhesion & migration
Cell Biology
Cell Culture
Cell migration
Cell Movement - drug effects
Cell Proliferation - drug effects
China
Drug resistance
Gene Expression Regulation, Neoplastic - drug effects
Humans
Immunology
Life Sciences
Male
Metastases
Middle Aged
Nuclear transport
Phagocytosis
Phosphoinositide Phospholipase C - metabolism
Phosphoinositide Phospholipase C - physiology
Phospholipase C
Prostate cancer
Prostatic Neoplasms - metabolism
Receptors, Androgen - metabolism
Receptors, Androgen - physiology
Signal transduction
Signal Transduction - drug effects
Signal Transduction - physiology
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Summary:Androgen receptor (AR) signaling is a major driver of prostate cancer (CaP). Although most therapies targeting AR are initially effective in CaP patients, drug resistance is inevitable, mainly because of the inappropriate re-activation of AR pathway. However, the underlying mechanisms remain largely unknown. Here, we found that phospholipase C epsilon (PLCɛ) was highly expressed in CaP samples, and was closely associated with AR signaling activities. PLCɛ depletion triggered enhanced autophagic activities via AMPK/ULK1 pathway, causing autophagy-mediated AR degradation and inhibition of AR nuclear translocation. This subsequently reduced AR signals in CaP and inhibited AR-driven cell migration/invasion. Furthermore, a positive correlation between PLCɛ and AR signaling activity was also observed in bicalutamide-resistant CaP samples and in AR-antagonist-resistant CaP cell models. PLCɛ depletion resulted in the failure to establish AR-antagonist-resistant CaP cell lines, and hindered the metastatic prowess of already established ones. These findings suggest that PLCɛ-mediated autophagic activity alteration is indispensible for the functionality of AR signaling and for CaP development.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-020-02917-9