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Volume 23
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10.3390/ijms23126520
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Article

The Unfolded Protein Response Sensor PERK Mediates Stiffness-Dependent Adaptation in Glioblastoma Cells

by
Mohammad Khoonkari
1,2,†,
Dong Liang
1,†,
Marina Trombetta Lima
3,
Tjitze van der Land
4,
Yuanke Liang
1,5,
Jianwu Sun
2,
Amalia Dolga
3,
Marleen Kamperman
2,
Patrick van Rijn
4,6,* and
Frank A. E. Kruyt
1,*
1
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
2
Polymer Science, Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
3
Department of Molecular Pharmacology, Faculty of Science and Engineering, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, The Netherlands
4
Department of Biomedical Engineering-FB40, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
5
Department of Thyroid and Breast Surgery, Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, 57 Changping Road, Shantou 515041, China
6
W.J. Kolff Institute for Biomedical Engineering and Materials Science-FB41, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Academic Editor: Boaz Tirosh
Int. J. Mol. Sci. 2022, 23(12), 6520; https://doi.org/10.3390/ijms23126520
Received: 18 May 2022 / Revised: 6 June 2022 / Accepted: 9 June 2022 / Published: 10 June 2022
(This article belongs to the Special Issue Study of Endoplasmic Reticulum Stress and Unfolded Protein Response)
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Abstract

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults. In addition to genetic causes, the tumor microenvironment (TME), including stiffening of the extracellular matrix (ECM), is a main driver of GBM progression. Mechano-transduction and the unfolded protein response (UPR) are essential for tumor-cell adaptation to harsh TME conditions. Here, we studied the effect of a variable stiff ECM on the morphology and malignant properties of GBM stem cells (GSCs) and, moreover, examined the possible involvement of the UPR sensor PERK herein. For this, stiffness-tunable human blood plasma (HBP)/alginate hydrogels were generated to mimic ECM stiffening. GSCs showed stiffness-dependent adaptation characterized by elongated morphology, increased proliferation, and motility which was accompanied by F-Actin cytoskeletal remodeling. Interestingly, in PERK-deficient GSCs, stiffness adaptation was severely impaired, which was evidenced by low F-Actin levels, the absence of F-Actin remodeling, and decreased cell proliferation and migration. This impairment could be linked with Filamin-A (FLN-A) expression, a known interactor of PERK, which was strongly reduced in PERK-deficient GSCs. In conclusion, we identified a novel PERK/FLNA/F-Actin mechano-adaptive mechanism and found a new function for PERK in the cellular adaptation to ECM stiffening. View Full-Text
Keywords: glioblastoma; extracellular matrix stiffening; tumor microenvironment; mechanical stress; PERK; unfolded protein response glioblastoma; extracellular matrix stiffening; tumor microenvironment; mechanical stress; PERK; unfolded protein response
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MDPI and ACS Style

Khoonkari, M.; Liang, D.; Lima, M.T.; van der Land, T.; Liang, Y.; Sun, J.; Dolga, A.; Kamperman, M.; van Rijn, P.; Kruyt, F.A.E. The Unfolded Protein Response Sensor PERK Mediates Stiffness-Dependent Adaptation in Glioblastoma Cells. Int. J. Mol. Sci. 2022, 23, 6520. https://doi.org/10.3390/ijms23126520

AMA Style

Khoonkari M, Liang D, Lima MT, van der Land T, Liang Y, Sun J, Dolga A, Kamperman M, van Rijn P, Kruyt FAE. The Unfolded Protein Response Sensor PERK Mediates Stiffness-Dependent Adaptation in Glioblastoma Cells. International Journal of Molecular Sciences. 2022; 23(12):6520. https://doi.org/10.3390/ijms23126520

Chicago/Turabian Style

Khoonkari, Mohammad, Dong Liang, Marina T. Lima, Tjitze van der Land, Yuanke Liang, Jianwu Sun, Amalia Dolga, Marleen Kamperman, Patrick van Rijn, and Frank A.E. Kruyt. 2022. "The Unfolded Protein Response Sensor PERK Mediates Stiffness-Dependent Adaptation in Glioblastoma Cells" International Journal of Molecular Sciences 23, no. 12: 6520. https://doi.org/10.3390/ijms23126520

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