Publication: Generation of TRAIL-resistant cell line models reveals distinct adaptive mechanisms for acquired resistance and re-sensitization
dc.contributor.coauthor | Esai Selvan, Myvizhi | |
dc.contributor.coauthor | Bhere, Deepak | |
dc.contributor.coauthor | Shah, Khalid | |
dc.contributor.department | School of Medicine | |
dc.contributor.department | Graduate School of Health Sciences | |
dc.contributor.department | Graduate School of Sciences and Engineering | |
dc.contributor.kuauthor | Cingöz, Ahmet | |
dc.contributor.kuauthor | Gümüş, Zeynep Hülya | |
dc.contributor.kuauthor | Morova, Tunç | |
dc.contributor.kuauthor | Önder, Tuğba Bağcı | |
dc.contributor.kuauthor | Özyerli, Ezgi | |
dc.contributor.kuauthor | Şeker-Polat, Fidan | |
dc.contributor.kuauthor | Solaroğlu, İhsan | |
dc.contributor.schoolcollegeinstitute | GRADUATE SCHOOL OF HEALTH SCIENCES | |
dc.contributor.schoolcollegeinstitute | GRADUATE SCHOOL OF SCIENCES AND ENGINEERING | |
dc.contributor.schoolcollegeinstitute | SCHOOL OF MEDICINE | |
dc.date.accessioned | 2024-11-09T22:49:39Z | |
dc.date.issued | 2021 | |
dc.description.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-kappa B pathway. Inhibiting NF-kappa B 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. | |
dc.description.indexedby | WOS | |
dc.description.indexedby | Scopus | |
dc.description.indexedby | PubMed | |
dc.description.issue | 18 | |
dc.description.openaccess | NO | |
dc.description.publisherscope | International | |
dc.description.sponsoredbyTubitakEu | N/A | |
dc.description.sponsorship | Scientific and Technological Research Council of Turkey (TUBITAK) [3501] | |
dc.description.sponsorship | Marie Curie FP7 Career Reintegration Grant (EC) [618673] | |
dc.description.sponsorship | BAGEP | |
dc.description.sponsorship | NIH/NCI [U24 CA210993] | |
dc.description.sponsorship | Icahn Institute | |
dc.description.sponsorship | NIH [R01CA201148] | |
dc.description.sponsorship | Presidency of Turkey, Presidency of Strategy and Budget 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 Koc University Research Center for Translational Medicine (KUTTAM), funded by the Presidency of Turkey, Presidency of Strategy and Budget. | |
dc.description.volume | 40 | |
dc.identifier.doi | 10.1038/s41388-021-01697-6 | |
dc.identifier.eissn | 1476-5594 | |
dc.identifier.issn | 0950-9232 | |
dc.identifier.scopus | 2-s2.0-85103166221 | |
dc.identifier.uri | https://doi.org/10.1038/s41388-021-01697-6 | |
dc.identifier.uri | https://hdl.handle.net/20.500.14288/6543 | |
dc.identifier.wos | 632820300004 | |
dc.language.iso | eng | |
dc.publisher | Springernature | |
dc.relation.ispartof | oncogene | |
dc.subject | Biochemistry | |
dc.subject | Molecular biology | |
dc.subject | Oncology | |
dc.subject | Cell biology | |
dc.subject | Genetics | |
dc.subject | Heredity | |
dc.title | Generation of TRAIL-resistant cell line models reveals distinct adaptive mechanisms for acquired resistance and re-sensitization | |
dc.type | Journal Article | |
dspace.entity.type | Publication | |
local.contributor.kuauthor | Cingöz, Ahmet | |
local.contributor.kuauthor | Özyerli, Ezgi | |
local.contributor.kuauthor | Morova, Tunç | |
local.contributor.kuauthor | Şeker-Polat, Fidan | |
local.contributor.kuauthor | Gümüş, Zeynep Hülya | |
local.contributor.kuauthor | Solaroğlu, İhsan | |
local.contributor.kuauthor | Önder, Tuğba Bağcı | |
local.publication.orgunit1 | GRADUATE SCHOOL OF HEALTH SCIENCES | |
local.publication.orgunit1 | GRADUATE SCHOOL OF SCIENCES AND ENGINEERING | |
local.publication.orgunit1 | SCHOOL OF MEDICINE | |
local.publication.orgunit2 | School of Medicine | |
local.publication.orgunit2 | Graduate School of Health Sciences | |
local.publication.orgunit2 | Graduate School of Sciences and Engineering | |
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