Publication

ER stress and UPR activation in glioblastoma: identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation

Penaranda-Fajardo, N. M., Meijer, C., Liang, Y., Dijkstra, B. M., Aguirre-Gamboa, R., den Dunnen, W. F. A. & Kruyt, F. A. E., 18-Sep-2019, In : Cell death & disease. 10, 16 p., 690.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Penaranda-Fajardo, N. M., Meijer, C., Liang, Y., Dijkstra, B. M., Aguirre-Gamboa, R., den Dunnen, W. F. A., & Kruyt, F. A. E. (2019). ER stress and UPR activation in glioblastoma: identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation. Cell death & disease, 10, [690]. https://doi.org/10.1038/s41419-019-1934-1

Author

Penaranda-Fajardo, Natalia M. ; Meijer, Coby ; Liang, Yuanke ; Dijkstra, Bianca M. ; Aguirre-Gamboa, Raul ; den Dunnen, Wilfred F. A. ; Kruyt, Frank A. E. / ER stress and UPR activation in glioblastoma : identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation. In: Cell death & disease. 2019 ; Vol. 10.

Harvard

Penaranda-Fajardo, NM, Meijer, C, Liang, Y, Dijkstra, BM, Aguirre-Gamboa, R, den Dunnen, WFA & Kruyt, FAE 2019, 'ER stress and UPR activation in glioblastoma: identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation', Cell death & disease, vol. 10, 690. https://doi.org/10.1038/s41419-019-1934-1

Standard

ER stress and UPR activation in glioblastoma : identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation. / Penaranda-Fajardo, Natalia M.; Meijer, Coby; Liang, Yuanke; Dijkstra, Bianca M.; Aguirre-Gamboa, Raul; den Dunnen, Wilfred F. A.; Kruyt, Frank A. E.

In: Cell death & disease, Vol. 10, 690, 18.09.2019.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Penaranda-Fajardo NM, Meijer C, Liang Y, Dijkstra BM, Aguirre-Gamboa R, den Dunnen WFA et al. ER stress and UPR activation in glioblastoma: identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation. Cell death & disease. 2019 Sep 18;10. 690. https://doi.org/10.1038/s41419-019-1934-1


BibTeX

@article{3e695a9ee74745bea3be33f529b26ada,
title = "ER stress and UPR activation in glioblastoma: identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation",
abstract = "Patients with aggressive brain tumors, named glioblastoma multiforme (GBM), have a poor prognoses. Here we explored if the ER stress/unfolded protein response (UPR) is involved in the pathophysiology of GBM and may provide novel therapeutic targets. Immunohistochemical analyses of a tissue microarray containing primary GBM specimens showed strong variability in expression of the UPR markers GRP78/BiP, XBP1, and ATF4. Interestingly, high ATF4 expression was associated with poor overall survival suggesting involvement of PERK signaling in GBM progression. In vitro experiments using patient-derived neurospheres, enriched for GBM stem cells (GSCs), showed high sensitivity for the ER stressor thapsigargin (Tg) mainly via PERK signaling. In contrast, neurospheres-derived differentiated GBM cells were less sensitive likely due to lower UPR activity as indicated by comparative transcriptional profiling. Tg and Tunicamycin strongly reduced neurosphere forming ability of GSCs that was linked with potent PERK-dependent downregulation of SOX2 protein. Interestingly, SOX2 downregulation occurred directly via PERK, not requiring downstream activation of the PERK-UPR pathway. Moreover, PERK inactivation resulted in aberrant serum-induced differentiation of GBM neurospheres accompanied by persistent SOX2 expression, delayed upregulation of GFAP and reduced cell adherence. In conclusion, we provide evidence that PERK signaling contributes to the prognoses of primary GBM patients and identified PERK as a novel regulator of SOX2 expression and GSC differentiation. The role of PERK appeared to be pleiotropic involving UPR-dependent, as well as novel identified noncanonical mechanisms regulating SOX2. ER stress and PERK modulation appear to provide promising therapeutic targets for therapy in GBM.",
keywords = "ENDOPLASMIC-RETICULUM, CANCER, GLIOMA, DEATH, PROLIFERATION, DISCOVERY, POTENT",
author = "Penaranda-Fajardo, {Natalia M.} and Coby Meijer and Yuanke Liang and Dijkstra, {Bianca M.} and Raul Aguirre-Gamboa and {den Dunnen}, {Wilfred F. A.} and Kruyt, {Frank A. E.}",
year = "2019",
month = "9",
day = "18",
doi = "10.1038/s41419-019-1934-1",
language = "English",
volume = "10",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - ER stress and UPR activation in glioblastoma

T2 - identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation

AU - Penaranda-Fajardo, Natalia M.

AU - Meijer, Coby

AU - Liang, Yuanke

AU - Dijkstra, Bianca M.

AU - Aguirre-Gamboa, Raul

AU - den Dunnen, Wilfred F. A.

AU - Kruyt, Frank A. E.

PY - 2019/9/18

Y1 - 2019/9/18

N2 - Patients with aggressive brain tumors, named glioblastoma multiforme (GBM), have a poor prognoses. Here we explored if the ER stress/unfolded protein response (UPR) is involved in the pathophysiology of GBM and may provide novel therapeutic targets. Immunohistochemical analyses of a tissue microarray containing primary GBM specimens showed strong variability in expression of the UPR markers GRP78/BiP, XBP1, and ATF4. Interestingly, high ATF4 expression was associated with poor overall survival suggesting involvement of PERK signaling in GBM progression. In vitro experiments using patient-derived neurospheres, enriched for GBM stem cells (GSCs), showed high sensitivity for the ER stressor thapsigargin (Tg) mainly via PERK signaling. In contrast, neurospheres-derived differentiated GBM cells were less sensitive likely due to lower UPR activity as indicated by comparative transcriptional profiling. Tg and Tunicamycin strongly reduced neurosphere forming ability of GSCs that was linked with potent PERK-dependent downregulation of SOX2 protein. Interestingly, SOX2 downregulation occurred directly via PERK, not requiring downstream activation of the PERK-UPR pathway. Moreover, PERK inactivation resulted in aberrant serum-induced differentiation of GBM neurospheres accompanied by persistent SOX2 expression, delayed upregulation of GFAP and reduced cell adherence. In conclusion, we provide evidence that PERK signaling contributes to the prognoses of primary GBM patients and identified PERK as a novel regulator of SOX2 expression and GSC differentiation. The role of PERK appeared to be pleiotropic involving UPR-dependent, as well as novel identified noncanonical mechanisms regulating SOX2. ER stress and PERK modulation appear to provide promising therapeutic targets for therapy in GBM.

AB - Patients with aggressive brain tumors, named glioblastoma multiforme (GBM), have a poor prognoses. Here we explored if the ER stress/unfolded protein response (UPR) is involved in the pathophysiology of GBM and may provide novel therapeutic targets. Immunohistochemical analyses of a tissue microarray containing primary GBM specimens showed strong variability in expression of the UPR markers GRP78/BiP, XBP1, and ATF4. Interestingly, high ATF4 expression was associated with poor overall survival suggesting involvement of PERK signaling in GBM progression. In vitro experiments using patient-derived neurospheres, enriched for GBM stem cells (GSCs), showed high sensitivity for the ER stressor thapsigargin (Tg) mainly via PERK signaling. In contrast, neurospheres-derived differentiated GBM cells were less sensitive likely due to lower UPR activity as indicated by comparative transcriptional profiling. Tg and Tunicamycin strongly reduced neurosphere forming ability of GSCs that was linked with potent PERK-dependent downregulation of SOX2 protein. Interestingly, SOX2 downregulation occurred directly via PERK, not requiring downstream activation of the PERK-UPR pathway. Moreover, PERK inactivation resulted in aberrant serum-induced differentiation of GBM neurospheres accompanied by persistent SOX2 expression, delayed upregulation of GFAP and reduced cell adherence. In conclusion, we provide evidence that PERK signaling contributes to the prognoses of primary GBM patients and identified PERK as a novel regulator of SOX2 expression and GSC differentiation. The role of PERK appeared to be pleiotropic involving UPR-dependent, as well as novel identified noncanonical mechanisms regulating SOX2. ER stress and PERK modulation appear to provide promising therapeutic targets for therapy in GBM.

KW - ENDOPLASMIC-RETICULUM

KW - CANCER

KW - GLIOMA

KW - DEATH

KW - PROLIFERATION

KW - DISCOVERY

KW - POTENT

U2 - 10.1038/s41419-019-1934-1

DO - 10.1038/s41419-019-1934-1

M3 - Article

VL - 10

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

M1 - 690

ER -

ID: 99702165