The anterior gradient homologue 2 (AGR2) co‑localises with the glucose‑regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analyses

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dc.cclicenceCC-BY-NCen
dc.contributor.authorHussein, Deema
dc.contributor.authorAlsereihi, Reem
dc.contributor.authorSalwati, Abdulla Ahmed A
dc.contributor.authorAlgehani, Rinad
dc.contributor.authorAlhowity, Alazouf
dc.contributor.authorAl‑Hejin, Ahmed M
dc.contributor.authorSchulten, Hans‑Juergen
dc.contributor.authorBaeesa, Saleh
dc.contributor.authorBangash, Mohammed
dc.contributor.authorAlghamdi, Fahad
dc.contributor.authorCross, Richard
dc.contributor.authorAl Zughaibi, Torki
dc.contributor.authorSaka, Mohamad
dc.contributor.authorChaudhary, Adeel
dc.contributor.authorAbuzenadah, Adel
dc.date.acceptance2022-12-08
dc.date.accessioned2023-02-27T16:48:58Z
dc.date.available2023-02-27T16:48:58Z
dc.date.issued2022-12-08
dc.descriptionopen access articleen
dc.description.abstractBackground: Glioblastomas (GBs) are characterised as one of the most aggressive primary central nervous system tumours (CNSTs). Single-cell sequencing analysis identified the presence of a highly heterogeneous population of cancer stem cells (CSCs). The proteins anterior gradient homologue 2 (AGR2) and glucose-regulated protein 78 (GRP78) are known to play critical roles in regulating unfolded protein response (UPR) machinery. The UPR machinery influences cell survival, migration, invasion and drug resistance. Hence, we investigated the role of AGR2 in drug-resistant recurrent glioblastoma cells. Methods: Immunofluorescence, biological assessments and whole exome sequencing analyses were completed under in situ and in vitro conditions. Cells were treated with CNSTs clinical/preclinical drugs taxol, cisplatin, irinotecan, MCK8866, etoposide, and temozolomide, then resistant cells were analysed for the expression of AGR2. AGR2 was repressed using single and double siRNA transfections and combined with either temozolomide or irinotecan. Results: Genomic and biological characterisations of the AGR2-expressed Jed66_GB and Jed41_GB recurrent glioblastoma tissues and cell lines showed features consistent with glioblastoma. Immunofluorescence data indicated that AGR2 co-localised with the UPR marker GRP78 in both the tissue and their corresponding primary cell lines. AGR2 and GRP78 were highly expressed in glioblastoma CSCs. Following treatment with the aforementioned drugs, all drug-surviving cells showed high expression of AGR2. Prolonged siRNA repression of a particular region in AGR2 exon 2 reduced AGR2 protein expression and led to lower cell densities in both cell lines. Co-treatments using AGR2 exon 2B siRNA in conjunction with temozolomide or irinotecan had partially synergistic effects. The slight reduction of AGR2 expression increased nuclear Caspase-3 activation in both cell lines and caused multinucleation in the Jed66_GB cell line. Conclusions: AGR2 is highly expressed in UPR-active CSCs and drug-resistant GB cells, and its repression leads to apoptosis, via multiple pathways.en
dc.funderNo external funderen
dc.identifier.citationHussein, D., Alsereihi, R., Salwati, A.A.A. et al. (2022). The anterior gradient homologue 2 (AGR2) co-localises with the glucose-regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analyses. Cancer Cell International. 22, 387en
dc.identifier.doihttps://doi.org/10.1186/s12935-022-02814-5
dc.identifier.issn1475-2867
dc.identifier.urihttps://hdl.handle.net/2086/22536
dc.language.isoen_USen
dc.peerreviewedYesen
dc.publisherSpringeren
dc.researchinstituteInstitute of Engineering Sciences (IES)en
dc.subjectAnterior gradient homologue 2 (AGR2)en
dc.subjectCancer stem cells (CSCs)en
dc.subjectDrug resistanceen
dc.subjectGlioblastomaen
dc.subjectGlucose-regulated protein 78 (GRP78)en
dc.titleThe anterior gradient homologue 2 (AGR2) co‑localises with the glucose‑regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analysesen
dc.typeArticleen

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