GPI-80 Augments NF-κB Activation in Tumor Cells.

Yuji Takeda,Nobuyuki Tanaka,Hiromi Ito,Shinichi Saitoh,Akemi Araki,Hironobu Asao,Yuta Kurota,Hidetoshi Nara,Tomoyuki Kato,Norihiko Tsuchiya

doi:10.3390/ijms222112027

Abstract

Recent studies have discovered a relationship between glycosylphosphatidylinositol (GPI)-anchored protein 80 (GPI-80)/VNN2 (80 kDa GPI-anchored protein) and malignant tumors. GPI-80 is known to regulate neutrophil adhesion; however, the action of GPI-80 on tumors is still obscure. In this study, although the expression of GPI-80 mRNA was detectable in several tumor cell lines, the levels of GPI-80 protein were significantly lower than that in neutrophils. To clarify the function of GPI-80 in tumor cells, GPI-80-expressing cells and GPI-80/VNN2 gene-deleted cells were established using PC3 prostate cancer cells. In GPI-80-expressing cells, GPI-80 was mainly detected in vesicles. Furthermore, soluble GPI-80 in the conditioned medium was associated with the exosome marker CD63 and was also detected in the plasma obtained from prostate cancer patients. Unexpectedly, cell adhesion and migration of GPI-80-expressing PC3 cells were not modulated by anti-GPI-80 antibody treatment. However, similar to the GPI-80 family molecule, VNN1, the pantetheinase activity and oxidative state were augmented in GPI-80-expressing cells. GPI-80-expressing cells facilitated non-adhesive proliferation, slow cell proliferation, NF-κB activation and IL-1β production. These phenomena are known to be induced by physiological elevation of the oxidative state. Thus, these observations indicated that GPI-80 affects various tumor responses related to oxidation.

Highlights

Molecular targeted drugs and immune checkpoint inhibitors have opened a new era of cancer therapy
NF-κB activation was facilitated in the GPI-80+ cell subset
The secreted soluble GPI-80 from PC3 cells was co-localized with exosome markers, and soluble GPI-80 was detected in the plasma of high-risk group prostate cancer patients

Summary

Introduction

Molecular targeted drugs and immune checkpoint inhibitors have opened a new era of cancer therapy. The molecular mechanisms of resistance to these therapies have been elucidated, effective strategies to prevent or treat resistant tumors are required to improve clinical outcomes for patients [2]. Various comprehensive analytical studies have identified many molecules associated with tumor formation and malignancy. Glycosylphosphatidylinositol (GPI)anchored protein (GPI-80 known as VNN2) has been identified as one of the molecules associated with chemotherapeutic resistance of tumors [3]. GPI-80 co-localizes with β2 integrin on resting neutrophils and is concentrated on pseudopodia during neutrophil migration [5]. Based on these observations, GPI-80 is considered to be a molecule that regulates adhesion on neutrophils. GPI-80 is considered to be a marker for hematopoietic stem cells

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Conclusion