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Targeting unfolded protein response using albumin-encapsulated nanoparticles attenuates temozolomide resistance in glioblastoma

British Journal of Cancer volume 128, pages 1955–1963 (2023)Cite this article

Subjects

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

Our study demonstrates modulation of ER stress by targeting PDI as a promising therapeutic rationale to overcome chemoresistance.

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Fig. 1: Inhibition of PDI attenuates TMZ resistance in vitro.
Fig. 2: Inhibition of PDI-sensitised glioblastoma cells upon TMZ treatment via UPR-mediated cell death in vitro.
Fig. 3: Characterisation of HSA-encapsulated CCF642 nanoparticles.
Fig. 4: PDI inhibition suppresses glioblastoma growth and attenuates TMZ resistance in vivo.
Fig. 5: Schematic diagram of the molecular mechanism underlying chronic ER stress-induced TMZ resistance.

Data availability

The data presented in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

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.

Funding

This work was supported by the Health and Medical Research Fund (HMRF), project no. 08191986, of the Food and Health Bureau (Hong Kong).

Author information

Authors and Affiliations

  1. Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China

    Karrie Mei-Yee Kiang, Wanjun Tang, Jiaxin Liu, Ning Li, Tsz-Lung Lam, Zhiyuan Zhu & Gilberto Ka-Kit Leung

  2. Department of Mechanical Engineering, The University of Hong Kong, Hong Kong SAR, China

    Qingchun Song & Ho Cheung Shum

  3. Department of Neurosurgery, Zhongda Hospital, Southeast University, Nanjing, China

    Ning Li

  4. Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Shatin, New Territories, Hong Hnog SAR, China

    Ho Cheung Shum

  5. Department of Functional Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China

    Zhiyuan Zhu

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  1. Karrie Mei-Yee Kiang
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Contributions

KK performed the experiments, wrote the original draft and involved in conceptualisation and funding acquisition. WT, JL and TL performed the experiments and provided technical support. QS and HS helped in the preparation of nanoparticles and provided technical support. NL participated in the formal data analyses. ZZ and GL supervised the entire study and provided critical review on the manuscript. All authors reviewed the final manuscript.

Corresponding authors

Correspondence to Zhiyuan Zhu or Gilberto Ka-Kit Leung.

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Competing interests

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

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