FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer

Abstract

Low-affinity immunoglobulin gamma Fc region receptor III-A (FccRIIIa) is a cell surface protein that belongs to a family of Fc receptors that facilitate the protective function of the immune system against pathogens. However, the role of FccRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FccRIIIa expression was present in PCa cells and its level was significantly higher in metastatic lesions than in primary tumors from the PCa cohort (P = 0.006). PCa patients with an elevated level of FccRIIIa expression had poorer biochemical recurrence (BCR)-free survival compared with those with lower FccRIIIa expression, suggesting that FccRIIIa is of clinical importance in PCa. We demonstrated that overexpression of FccRIIIa increased the proliferative ability of PCa cell line C4-2 cells, which was accompanied by the upregulation of androgen receptor (AR) and phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Ka), which are the key players in controlling PCa progression. Conversely, targeted inhibition of FccRIIIa via siRNA-mediated knockdown or using its inhibitory antibody suppressed growth of xenograft PC-3 and PC-3M prostate tumors and reduced distant metastasis in xenograft mouse models. We further showed that elevated expression of AR enhanced FccRIIIa expression, whereas inhibition of AR activity using enzalutamide led to a significant downregulation of FccRIIIa protein expression. Similarly, inhibition of PIP5K1a decreased FccRIIIa expression Abbreviations ALDH, aldehyde dehydrogenases; AR, androgen receptor; ARE-Luc vector, androgen-responsive element luciferase vector; BPH, benign prostate hyperplasia; BRFS, biochemical recurrence-free survival; CRPC, castration-resistant prostate cancer; DHT, dihydrotestosterone; FccRIIIa, low-affinity immunoglobulin gamma Fc region receptor III-A; GDPR, The General Data Protection Regulation; PCa, prostate cancer; PIP2, phosphatidylinositol-4,5-P 2 ; PIP5K1a, phosphatidylinositol-4-phosphate 5-kinase type-1 alpha.

Molecular landscape for risk prediction and personalized therapeutics of castration-resistant prostate cancer: at a glance

“…For example, USP16, KDM4B, and RNF8 could regulate AR signaling by mediating the expression of c-myc (6)(7)(8). Interestingly, Larsson et al found that FcgRIIIa receptors could interact with AR receptors and affect the progression of CRPC in xenograft mouse models (9). COP1 promoted GATA2 degradation to inhibit AR expression and activation (10), however, Shen et al found that MAPK4 activated GATA2 to regulate AR transcription in mice (11).…”

“…Interestingly, Larsson et al. found that FcγRIIIa receptors could interact with AR receptors and affect the progression of CRPC in xenograft mouse models ( 9 ). COP1 promoted GATA2 degradation to inhibit AR expression and activation ( 10 ), however, Shen et al.…”

“…For example, the overexpression of RON could activate multiple transcription factors, and it promoted AR activation of AR response genes and nuclear localization ( 73 ). FcγRIIIa facilitated the growth and metastasis of PCa by regulating the AR and PIP5K1α pathways ( 9 ). TLX plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence, and it could confer resistance to androgen deprivation and anti-androgen ( 74 ).…”