Targeting <scp>XBP1 mRNA</scp> splicing sensitizes glioblastoma to chemotherapy

Dowdell, Amiee; Marsland, Mark; Faulkner, Sam; Gedye, Craig; Griffin, Cassandra; Marsland, Joanne; Jiang, Chen Chen; Hondermarck, Hubert

doi:10.1096/fba.2022-00141

Cited by 2 publications

(1 citation statement)

References 37 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additional RNA-binding proteins found to promote temozolomide resistance include FXR1 (Wei et al, 2022), ADAR3 (Raghava Kurup et al, 2022), NSUN5 (Zhou et al, 2023), RRM2 (Perrault et al, 2023) and MEX3A (Gan et al, 2022). Regarding mRNA alternative splicing, dysregulation of the process is associated with resistance against temozolomide in glioblastoma (Dowdell et al, 2023, Tiek et al, 2022). Among splicing components, the splicing factors FBXO7 and SRSF4 have been identified to facilitate temozolomide resistance of the brain tumor spheroids (Li et al, 2023, Sun et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

KHDRBS3 facilitates self-renewal and temozolomide resistance of glioblastoma cell lines

Somrit,

Krobthong,

Yingchutrakul

et al. 2024

Preprint

View full text Add to dashboard Cite

Glioblastoma is a deadly tumor which possesses glioblastoma stem cell populations involved in temozolomide resistance. To gain insight into the mechanisms of self-renewing and therapy-resistant cancer stem cells, subcellular proteomics was utilized to identify proteins whose expression is enriched in U251-derived glioblastoma stem-like cells. The RNA binding protein KHDRBS3 was successfully identified as a gene up-regulated in the cancer stem cell population compared with its differentiated derivatives. Depletion of KHDRBS3 by RNA silencing led to a decrease in cell proliferation, neurosphere formation, migration, and expression of genes involved in glioblastoma stemness. Importantly, temozolomide sensitivity can be induced by the gene knockdown. Collectively, our results highlight KHDRBS3 as a novel factor associated with self-renewal of glioblastoma stem-like cells and temozolomide resistance. As a consequence, targeting KHDRBS3 may help eradicate glioblastoma stem-like cells.

show abstract

Section: Discussionmentioning

confidence: 99%

KHDRBS3 facilitates self-renewal and temozolomide resistance of glioblastoma cell lines

Somrit,

Krobthong,

Yingchutrakul

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Expression of key unfolded protein response genes predicts patient survival and an immunosuppressive microenvironment in glioblastoma

Oliveira,

de Campos,

Pereira

et al. 2024

transl med commun

View full text Add to dashboard Cite

Background Dysregulation of cellular processes related to protein folding and trafficking leads to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), triggering ER stress. Cells cope with ER stress by activating the unfolded protein response (UPR), a signaling pathway that has been implicated in a variety of diseases, including cancer. However, the role of the UPR in cancer initiation and progression is still unclear. Methods Here we used bulk and single cell RNA sequencing data to investigate ER stress-related gene expression in glioblastoma, as well as the impact key UPR genes have on patient survival. Results ER stress-related genes are highly expressed in both cancer cells and tumor-associated macrophages, with evidence of high intra- and inter-tumor heterogeneity. High expression of the UPR-related genes HSPA5, P4HB, and PDIA4 was identified as risk factors while high MAPK8 (JNK1) expression was identified as a protective factor in glioblastoma patients, indicating UPR genes have prognostic potential in this cancer type. Finally, expression of XBP1 and MAPK8, two key downstream targets of the ER sentinel IRE1α, correlates with the presence of immune cell types associated with immunosuppression and a worse patient outcome. This suggests that the expression of these genes is associated with an immunosuppressive tumor microenvironment and uncover a potential link between stress response pathways, tumor microenvironment and glioblastoma patient survival. Conclusions We performed a comprehensive transcriptional characterization of the unfolded protein response in glioblastoma patients and identified UPR-related genes associated with glioblastoma patient survival, providing potential prognostic and predictive biomarkers as well as promising targets for developing new therapeutic interventions in glioblastoma treatment.

show abstract

Targeting XBP1 mRNA splicing sensitizes glioblastoma to chemotherapy

Cited by 2 publications

References 37 publications

KHDRBS3 facilitates self-renewal and temozolomide resistance of glioblastoma cell lines

KHDRBS3 facilitates self-renewal and temozolomide resistance of glioblastoma cell lines

Expression of key unfolded protein response genes predicts patient survival and an immunosuppressive microenvironment in glioblastoma

Contact Info

Product

Resources

About