Abstract
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.
Highlights
Prostate cancer (CaP) is one of the most common types of malignancies in males, ranking first in estimated new cancer cases and third in cancer-related deaths among males in the US1
We demonstrated that PLCɛ could regulate Androgen receptor (AR) protein degradation and AR nuclear translocation, both of which were achieved through AMPK/ULK1-mediated selective autophagy
The invasion abilities of LNCaP-Bica-R and wild-type LNCaP cultured with or without bicalutamide did not differ significantly, but they were all inhibited by PLCɛdepletion (Fig. 8c, d). These results suggest that PLCɛ/AR pathway is tightly associated with the metastatic property of bicalutamide-resistant CaP
Summary
Prostate cancer (CaP) is one of the most common types of malignancies in males, ranking first in estimated new cancer cases and third in cancer-related deaths among males in the US1. Therapeutics targeting the AR signaling have been extensively explored and widely used in Phospholipase C epsilon (PLCɛ) is a member of the PLC family of enzymes. PLCɛ is unique in relation to other members of PLC family: it receives signaling inputs from both heterotrimeric G proteins and Ras/Rho small GTPases. It is able to mediate sustained signaling via the generation of DAG in response to ligands that activate receptors coupled to Rho/Gα12/136. Owing to its interaction with Ras family proteins, PLCɛ is generally deemed a tumor promoter. A large number of studies have revealed the promoting role of PLCɛ in tumor development in a variety of cancer types[7,8,9,10].
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