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Serglycin Cooperates with the Unfolded Protein Response Pathway and Inflammation to Drive Glioblastoma Cell Survival

Athanasopoulos, Eleftherios N. ; Gialeli, Chrysostomi LU ; Natsiou, Angeliki ; Manou, Dimitra ; Labropoulou, Vassiliki T. and Theocharis, Achilleas D. (2026) In Cells 15(8).
Abstract

Serglycin (SRGN) has been found overexpressed and secreted in glioblastoma (GBM), associated with tumorigenic signaling and poor prognosis. In this study, we aimed to elucidate the involvement of SRGN in the unfolded protein response (UPR), an oncogenic signaling pathway implicated in protein recycling and cell fate. Herein, we developed stably transduced LN-18shSCR GBM cells, expressing high levels of SRGN, and SRGN-depleted LN-18shSRGN cells. We observed significantly attenuated expression and activity of all UPR mediators upon SRGN suppression, in particular PERK, IRE1, ATF6 and downstream effectors. SRGN-expressing cells possessed a constitutively active UPR, as indicated by its active phosphorylation status... (More)

Serglycin (SRGN) has been found overexpressed and secreted in glioblastoma (GBM), associated with tumorigenic signaling and poor prognosis. In this study, we aimed to elucidate the involvement of SRGN in the unfolded protein response (UPR), an oncogenic signaling pathway implicated in protein recycling and cell fate. Herein, we developed stably transduced LN-18shSCR GBM cells, expressing high levels of SRGN, and SRGN-depleted LN-18shSRGN cells. We observed significantly attenuated expression and activity of all UPR mediators upon SRGN suppression, in particular PERK, IRE1, ATF6 and downstream effectors. SRGN-expressing cells possessed a constitutively active UPR, as indicated by its active phosphorylation status and accumulated pool of nuclear ATF4 in LN-18shSCR cells. Constitutive activation of the caspase-dependent apoptotic pathway was apparent in LN-18shSRGN cells. Induction of endoplasmic reticulum (ER) stress pointed out that LN-18shSRGN cells were predisposed to ER stress-associated cell death, whereas LN-18shSCR cells activated adaptive UPR signaling and displayed resistance to apoptosis. The evaluation of TLRs, TNFRs, ILs and NF-kB also underscored that SRGN is essential for their expression and active inflammatory signaling. We concluded that SRGN-expressing cells acquire a pro-survival UPR mechanism, highlighting the novel regulatory role of SRGN in the adaptation and survival of GBM cells.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
apoptosis, extracellular matrix, glioblastoma, inflammation, proteoglycans, serglycin, unfolded protein response
in
Cells
volume
15
issue
8
article number
660
publisher
MDPI AG
external identifiers
  • scopus:105037059000
  • pmid:42041528
ISSN
2073-4409
DOI
10.3390/cells15080660
language
English
LU publication?
yes
id
015c873b-c384-4e7a-8cae-f38d00b02b06
date added to LUP
2026-05-27 10:08:08
date last changed
2026-06-10 11:32:29
@article{015c873b-c384-4e7a-8cae-f38d00b02b06,
  abstract     = {{<p>Serglycin (SRGN) has been found overexpressed and secreted in glioblastoma (GBM), associated with tumorigenic signaling and poor prognosis. In this study, we aimed to elucidate the involvement of SRGN in the unfolded protein response (UPR), an oncogenic signaling pathway implicated in protein recycling and cell fate. Herein, we developed stably transduced LN-18<sup>shSCR</sup> GBM cells, expressing high levels of SRGN, and SRGN-depleted LN-18<sup>shSRGN</sup> cells. We observed significantly attenuated expression and activity of all UPR mediators upon SRGN suppression, in particular PERK, IRE1, ATF6 and downstream effectors. SRGN-expressing cells possessed a constitutively active UPR, as indicated by its active phosphorylation status and accumulated pool of nuclear ATF4 in LN-18<sup>shSCR</sup> cells. Constitutive activation of the caspase-dependent apoptotic pathway was apparent in LN-18<sup>shSRGN</sup> cells. Induction of endoplasmic reticulum (ER) stress pointed out that LN-18<sup>shSRGN</sup> cells were predisposed to ER stress-associated cell death, whereas LN-18<sup>shSCR</sup> cells activated adaptive UPR signaling and displayed resistance to apoptosis. The evaluation of TLRs, TNFRs, ILs and NF-kB also underscored that SRGN is essential for their expression and active inflammatory signaling. We concluded that SRGN-expressing cells acquire a pro-survival UPR mechanism, highlighting the novel regulatory role of SRGN in the adaptation and survival of GBM cells.</p>}},
  author       = {{Athanasopoulos, Eleftherios N. and Gialeli, Chrysostomi and Natsiou, Angeliki and Manou, Dimitra and Labropoulou, Vassiliki T. and Theocharis, Achilleas D.}},
  issn         = {{2073-4409}},
  keywords     = {{apoptosis; extracellular matrix; glioblastoma; inflammation; proteoglycans; serglycin; unfolded protein response}},
  language     = {{eng}},
  number       = {{8}},
  publisher    = {{MDPI AG}},
  series       = {{Cells}},
  title        = {{Serglycin Cooperates with the Unfolded Protein Response Pathway and Inflammation to Drive Glioblastoma Cell Survival}},
  url          = {{http://dx.doi.org/10.3390/cells15080660}},
  doi          = {{10.3390/cells15080660}},
  volume       = {{15}},
  year         = {{2026}},
}