The splicing FK506-binding protein-51 isoform plays a role in glioblastoma resistance through programmed cell death ligand-1 expression regulation

Abstract

Gliomas aberrantly express programmed cell death ligand-1 (PD-L1), which has a pivotal role in immunoevasion. The splicing isoform of FKBP5, termed FKBP51s, is a PD-L1 foldase, assisting the immune checkpoint molecule in maturation and expression on the plasma membrane. The concept that PD-L1 supports tumor-intrinsic properties is increasingly emerging. The aim of the present work was to confirm the pro-tumoral effect of PD-L1 on human glioma cell survival, stemness capacity and resistance, and to address the issue of whether, by targeting its foldase either chemically or by silencing, the aggressive tumor features could be attenuated. PD-L1-depleted glioma cells have a reduced threshold for apoptosis, while PD-L1 forced expression increases resistance. Similar results were obtained with FKBP51s modulation. The ability of PD-L1 to counteract cell death was hampered by FKBP51s silencing. PD-L1 expression was particularly high in glioma cells with a cancer-stem-cell profile. Moreover, PD-L1 sustained the spheroid formation capability of glioma cells. Targeting of FKBP51s by small-interfering RNA (siRNA) or the specific inhibitor SAFit2, reduced the number of formed spheroids, along with PD-L1 expression. Finally, in an orthotopic mouse model of glioblastoma, daily treatment with SAFit2 significantly reduced tumor PD-L1 expression, and tumor growth. In treated mice, caspase-3 activation and reduced vimentin expression were observed in excised tumors. In conclusion, targeting of FKBP51s hampers PD-L1 and its pro-tumoral properties, thereby affecting the self-renewal and growth capacities of glioblastoma cells in vitro and in vivo.

Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors

“…TLC (CH/EA = 2:1 + 1% HCOOH, v/v/ v): R f = 0.34. 1 (24). The substrate 22a (400 mg, 0.99 mmol, 1.00 equiv) was applied to general procedure A with K 2 CO 3 (409 mg, 2.96 mmol, 3.00 equiv) and 4bromo-1-butene (532 mg, 3.94 mmol, 4.00 equiv) in MeCN (20 mL).…”

“…The recent discovery of the first FKBP51-selective ligands (SAFit1 and SAFit2) provided powerful tools to study the role of FKBP51 in cellular and animal models. ,,,− A newly discovered transient binding pocket is the key to selectivity for FKBP51 over the highly homologous FKBP52. ,− Nevertheless, SAFit1 and SAFit2 are far from becoming drug candidates due to their high molecular weight and the associated poor physicochemical properties . Additionally, the binding site of FKBP51 is shallow and the creation of low molecular mass inhibitors with high ligand efficiency and sufficient potency is extremely challenging. ,− …”

Oncogenic magnesium transporter 1 upregulates programmed death-1-ligand 1 expression and contributes to growth and radioresistance of glioma cells through the ERK/MAPK signaling pathway

“…suggested anti-PD-L1 antibody to be a contributor to radiation-induced abscopal response via direct macrophage activation in glioblastoma [ 33 ]. Suppression of PD-L1 and its pro-tumoral activities has been unveiled to modulate the self-renewal and growth capacities of glioma cells, thus conferring a role in glioma resistance [ 34 ]. In line with the prior documentation, our in vivo experiments substantiated that MAGT1 could enhance the expression of PD-L1 by activating the ERK signaling pathway, thereby contributing to the growth and radio-resistance of glioma cells.…”

Current Progress in Cancer Immunotherapies Using Small Molecules Targeting PD-L1 Stability

“…Selective small molecule inhibitors of FKBP51S, namely, SAFit 1 and SAFit 2, were also demonstrated to modulate the post-translational modifications by impeding PD-L1 glycosylation, which led to decreased PD-L1 plasma membrane protein levels in glioblastoma cell lines [22]. In another study, SAFit2 treatment significantly decreased PD-L1 expression and consequently the tumor growth, in addition to negating the upregulation of PD-L1 expression upon ionizing radiation, which is frequently used as a glioma treatment [48]. Consequently, the SMIs of FKBP51S are considered attractive targets to relieve the PD-L1-induced immune evasion, particularly in the tumors with upregulated PD-L1 protein levels upon radiation treatment.…”