Abstract
The first-line treatment for prostate cancer (PCa) is androgen ablation therapy. However, prostate tumors generally recur and progress to androgen-independent PCa (AIPC) within 2–3 years. α-Actinin-4 (ACTN4) is an actin-binding protein that belongs to the spectrin gene superfamily and acts as an oncogene in various cancer types. Although ACTN4 is involved in tumorigenesis and the epithelial–mesenchymal transition of cervical cancer, the role of ACTN4 in PCa remains unknown. We found that the ACTN4 expression level increased during the transition from androgen-dependent PCa to AIPC. ACTN4 overexpression resulted in enhanced proliferation and motility of PCa cells. Increased β-catenin due to ACTN4 promoted the transcription of genes involved in proliferation and metastasis such as CCND1 and ZEB1. ACTN4-overexpressing androgen-sensitive PCa cells were able to grow in charcoal-stripped media. In contrast, ACTN4 knockdown using si-ACTN4 and ACTN4 nanobody suppressed the proliferation, migration, and invasion of AIPC cells. Results of the xenograft experiment revealed that the mice injected with LNCaPACTN4 cells exhibited an increase in tumor mass compared with those injected with LNCaPMock cells. These results indicate that ACTN4 is involved in AIPC transition and promotes the progression of PCa.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed cancer, which accounts for 42% of all cancer cases in the United States (Siegel et al, 2017)
ACTN4 contributes to aggressiveness and metastasis of various cancers (Honda, 2015); we investigated whether ACTN4 plays a role in the progression of PCa
Interaction between ACTN4 and androgen receptor (AR) was predicted by protein–protein binding analysis (Capaia et al, 2018); we examined whether ACTN4 is involved in the regulation of androgendependent PCa to androgen-independent PCa (AIPC) transition
Summary
Prostate cancer (PCa) is the most commonly diagnosed cancer, which accounts for 42% of all cancer cases in the United States (Siegel et al, 2017). The androgen receptor (AR) plays an important role in the development of early stage PCa. Upon binding of an androgen, AR is translocated into the nucleus and binds to the androgen receptor elements (AREs) in the promoters of target genes involved in cell proliferation and survival (Tan et al, 2015). Androgen deprivation therapy is the first-line treatment of PCa patients with local or metastatic prostate tumors; tumors relapse to AIPC or castration-resistant PCa (CRPC) within 2–3 years (Widmark et al, 2009; Warde et al, 2011). The progression of CRPC is very aggressive and metastatic (Katsogiannou et al, 2015).
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