α-Actinin-4 Promotes the Progression of Prostate Cancer Through the Akt/GSK-3β/β-Catenin Signaling Pathway

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.

Hemin accumulation and identification of a heme‐binding protein clan in K562 cells by proteomic and computational analysis

“…Recent studies have also correlated ACTN4 with some additional, somehow unexpected pleiotropic signaling roles. Epigenetically, ACTN4 has been found to act as a transcriptional co‐activator of the Akt/GSK‐3β/β‐catenin pathway (S. Park et al, 2020) and the p65 subunit of NF‐κΒ (Aksenova et al, 2013). Moreover, it also acts as a regulator of nuclear mRNA metabolism (Khotin et al, 2010) through the binding to the promoter of the cytochrome c gene upon muscle differentiation (Goffart et al, 2006), and the regulation of CYP1A1 gene expression (Poch et al, 2004).…”

Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

“…In mammalian cells, both LIMK 1 and LIMK 2 are found in the nucleus. As in cytoplasmic signaling, Rho GTPases also function in nuclear signaling, especially in DNA damage/repair, a process in which cofilin has also been implicated [250], so a pathway for LIMK phospho-activation via a Rho GTPase effector such as ROCK/PAK likely mediates the aspects of this process [251] (Figure 8). Surprisingly, evidence suggests LIMK1 and LIMK2 affect nuclear function but in opposite directions, with an imbalance proposed to affect cell proliferation and metastasis in some cancers [252,253].…”

Emerging Proteins in CRPC: Functional Roles and Clinical Implications

“…It was shown that ACTN4 expression level was higher in DU145 cells and PC-3 cells than in LNCaP cells (8). Sungyeon Park et al also verified that the protein level of ACTN4 was increased in LNCaP-AI cells compared with LNCaP cells (23). A previous study reported that ACTN4 interacts with glucocorticoid receptor and plays a role in glucocorticoid receptor activation (51).…”

“…Some proteins have been found expressed differently between CSPC and CRPC by traditional techniques such as WB. ACTN4, a member of the spectrin gene superfamily, always acts as an oncogene in various cancer types (23). To identify novel therapeutic targets for CRPC, Yu Ishizuya et al applied WB to examine the expression of ACTN4 in four prostate cancer cell lines (8).…”