Chemoresistant cancer cells frequently exhibit a state of chronically activated endoplasmic reticulum (ER) stress. Engaged with ER stress, the unfolded protein response (UPR) is an adaptive reaction initiated by the accumulation of misfolded proteins. Protein disulfide isomerase (PDI) is a molecular chaperone known to be highly expressed in glioblastomas with acquired resistance to temozolomide (TMZ). We investigate whether therapeutic targeting of PDI provides a rationale to overcome chemoresistance.
The activity of PDI was suppressed in glioblastoma cells using a small molecule inhibitor CCF642. Either single or combination treatment with TMZ was used. We prepared nanoformulation of CCF642 loaded in albumin as a drug carrier for orthotopic tumour model.
Inhibition of PDI significantly enhances the cytotoxic effect of TMZ on glioblastoma cells. More importantly, inhibition of PDI is able to sensitise glioblastoma cells that are initially resistant to TMZ treatment. Nanoformulation of CCF642 is well-tolerated and effective in suppressing tumour growth. It activates cell death-triggering UPR beyond repair and induces ER perturbations through the downregulation of PERK signalling. Combination treatment of TMZ with CCF642 significantly reduces tumour growth compared with either modality alone.
Our study demonstrates modulation of ER stress by targeting PDI as a promising therapeutic rationale to overcome chemoresistance.
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The data presented in this study are available from the corresponding author upon reasonable request.
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This work was supported by the Health and Medical Research Fund (HMRF), project no.08191986, of the Food and Health Bureau (Hong Kong). We would like to thank the University of Hong Kong LKS Faculty of Medicine the Centre of PanorOmic Sciences (Imaging and flow cytometry core), and the Electron Microscope Unit for their assistance and services.
This work was supported by the Health and Medical Research Fund (HMRF), project no. 08191986, of the Food and Health Bureau (Hong Kong).
HCS is a scientific advisor of EN Technology Limited in which he owns some equity, and also a managing director of the research centre, namely Advanced Biomedical Instrumentation Centre Limited. The works in the paper are however not directly related to the works of these two entities, as far as we know. The remaining authors declare no competing interests.
Ethics approval and consent to participate
Animal work was performed according to guidelines approved by the Committee on the Use of Live Animal for Teaching and Research, The University of Hong Kong. The use of animals and all experimental procedures were conducted in compliance to ARRIVE guidelines.
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Kiang, K.MY., Tang, W., Song, Q. et al. Targeting unfolded protein response using albumin-encapsulated nanoparticles attenuates temozolomide resistance in glioblastoma. Br J Cancer 128, 1955–1963 (2023). https://doi.org/10.1038/s41416-023-02225-x