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Generation of TRAIL-resistant cell line models reveals distinct adaptive mechanisms for acquired resistance and re-sensitization

Oncogene volume 40, pages 3201–3216 (2021)Cite this article

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04 March 2024 Editor's note: Readers are alerted that concerns have been raised regarding the reliability of data presented in this article. Further editorial action will be taken if appropriate once the investigation into the concerns is complete and all parties have been given an opportunity to respond in full.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumor cell-specific apoptosis, making it a prime therapeutic candidate. However, many tumor cells are either innately TRAIL-resistant, or they acquire resistance with adaptive mechanisms that remain poorly understood. In this study, we generated acquired TRAIL resistance models using multiple glioblastoma (GBM) cell lines to assess the molecular alterations in the TRAIL-resistant state. We selected TRAIL-resistant cells through chronic and long-term TRAIL exposure and noted that they showed persistent resistance both in vitro and in vivo. Among known TRAIL-sensitizers, proteosome inhibitor Bortezomib, but not HDAC inhibitor MS-275, was effective in overcoming resistance in all cell models. This was partly achieved through upregulating death receptors and pro-apoptotic proteins, and downregulating major anti-apoptotic members, Bcl-2 and Bcl-xL. We showed that CRISPR/Cas9 mediated silencing of DR5 could block Bortezomib-mediated re-sensitization, demonstrating its critical role. While overexpression of Bcl-2 or Bcl-xL was sufficient to confer resistance to TRAIL-sensitive cells, it failed to override Bortezomib-mediated re-sensitization. With RNA sequencing in multiple paired TRAIL-sensitive and TRAIL-resistant cells, we identified major alterations in inflammatory signaling, particularly in the NF-κB pathway. Inhibiting NF-κB substantially sensitized the most resistant cells to TRAIL, however, the sensitization effect was not as great as what was observed with Bortezomib. Together, our findings provide new models of acquired TRAIL resistance, which will provide essential tools to gain further insight into the heterogeneous therapy responses within GBM tumors. Additionally, these findings emphasize the critical importance of combining proteasome inhibitors and pro-apoptotic ligands to overcome acquired resistance.

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Fig. 1: Isolation and characterization of TRAIL-resistant sub-populations of GBM cell lines.
Fig. 2: Bortezomib can restore sensitivity in TRAIL-resistant subpopulations.
Fig. 3: Apoptosis is activated upon Bortezomib-mediated TRAIL sensitization in TRAIL-resistant cells.
Fig. 4: DR5 expression is critical for sensitivity and re-sensitization of GBM cells.
Fig. 5: Bcl-2 or Bcl-xL expression is critical in TRAIL-response but cannot block Bortezomib-mediated TRAIL sensitization.
Fig. 6: TRAIL-resistant subpopulations survive under long term TRAIL treatment.
Fig. 7: RNA-seq analysis of TRAIL-resistant subpopulations.
Fig. 8: Model of acquired TRAIL resistance and re-sensitization.

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  • 04 March 2024

    Editor's note: Readers are alerted that concerns have been raised regarding the reliability of data presented in this article. Further editorial action will be taken if appropriate once the investigation into the concerns is complete and all parties have been given an opportunity to respond in full.

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Acknowledgements

Financial support was obtained from The Scientific and Technological Research Council of Turkey (TUBITAK) (3501), Marie Curie FP7 Career Reintegration Grant (EC Grant # 618673), and BAGEP. ZHG and ME acknowledge NIH/NCI U24 CA210993 and start-up funds from the Icahn Institute. KS acknowledges the NIH R01CA201148. The authors gratefully acknowledge the use of services and facilities of the Koç University Research Center for Translational Medicine (KUTTAM), funded by the Presidency of Turkey, Presidency of Strategy and Budget.

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Authors and Affiliations

  1. Brain Cancer Research and Therapy Laboratory, Koç University Research Center for Translational Medicine, Istanbul, 34450, Turkey

    Ahmet Cingöz, Ezgi Ozyerli-Goknar, Fidan Seker-Polat & Tugba Bagci-Onder

  2. Koç University School of Medicine, Istanbul, 34450, Turkey

    Ahmet Cingöz, Ezgi Ozyerli-Goknar, Tunc Morova, Fidan Seker-Polat, Zeynep Hülya Gümüş, Ihsan Solaroglu & Tugba Bagci-Onder

  3. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Myvizhi Esai Selvan & Zeynep Hülya Gümüş

  4. Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Myvizhi Esai Selvan & Zeynep Hülya Gümüş

  5. Center for Stem Cell Therapeutics and Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Deepak Bhere & Khalid Shah

  6. Department of Neurosurgery, Koç University School of Medicine, Istanbul, 34010, Turkey

    Ihsan Solaroglu

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KS owns equity in and is a member of the Board of Directors of AMASA Therapeutics, a company developing stem cell-based therapies for cancer. KS’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies.

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Cingöz, A., Ozyerli-Goknar, E., Morova, T. et al. Generation of TRAIL-resistant cell line models reveals distinct adaptive mechanisms for acquired resistance and re-sensitization. Oncogene 40, 3201–3216 (2021). https://doi.org/10.1038/s41388-021-01697-6

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