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

Larsson, Per Flodbring; Karlsson, Richard; Sarwar, Martuza; Miftakhova, Regina; Wang, Tianyan; Syed Khaja, Azharuddin Sajid; Semenas, Julius; Chen, Sa; Hedblom, Andreas; Ali, Amjad; Ekström‐Holka, Kristina; Simoulis, Athanasios; Kumar, Anjani; Wingren, Anette Gjörloff; Robinson, Brian; Nyunt Wai, Sun; Mongan, Nigel P.; Heery, David M.; Öhlund, Daniel; Grundström, Thomas; Ødum, Niels; Persson, Jenny L.

Abstract

Low-affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) 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 FcγRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FcγRIIIa 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 FcγRIIIa expression had poorer biochemical recurrence (BCR)-free survival compared with those with lower FcγRIIIa expression, suggesting that FcγRIIIa is of clinical importance in PCa. We demonstrated that overexpression of FcγRIIIa 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 (PIP5Kα), which are the key players in controlling PCa progression. Conversely, targeted inhibition of FcγRIIIa 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 FcγRIIIa expression, whereas inhibition of AR activity using enzalutamide led to a significant downregulation of FcγRIIIa protein expression. Similarly, inhibition of PIP5K1α decreased FcγRIIIa expression in PCa cells. FcγRIIIa physically interacted with PIP5K1α and AR via formation of protein–protein complexes, suggesting that FcγRIIIa is functionally associated with AR and PIP5K1α in PCa cells. Our study identified FcγRIIIa as an important factor in promoting PCa growth and invasion. Further, the elevated activation of FcγRIII and AR and PIP5K1α pathways may cooperatively promote PCa growth and invasion. Thus, FcγRIIIa may serve as a potential new target for improved treatment of metastatic and castration-resistant PCa.

Citation

Larsson, P. F., Karlsson, R., Sarwar, M., Miftakhova, R., Wang, T., Syed Khaja, A. S., …Persson, J. L. (2022). FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer. Molecular Oncology, https://doi.org/10.1002/1878-0261.13166

• Journal Article Type: Article
• Acceptance Date: Dec 2, 2021
• Online Publication Date: Dec 21, 2021
• Publication Date: Jan 1, 2022
• Deposit Date: Jan 7, 2022
• Publicly Available Date: Jan 11, 2022
• Journal: Molecular Oncology
• Print ISSN: 1574-7891
• Electronic ISSN: 1878-0261
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1002/1878-0261.13166
• Keywords: Cancer Research; Genetics; Molecular Medicine; General Medicine; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/7170964
• Publisher URL: https://febs.onlinelibrary.wiley.com/doi/10.1002/1878-0261.13166
• Additional Information: Received: 2021-07-07; Accepted: 2021-12-02; Published: 2021-12-21