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

dc.contributor.coauthorEsai Selvan, Myvizhi
dc.contributor.coauthorBhere, Deepak
dc.contributor.coauthorShah, Khalid
dc.contributor.departmentSchool of Medicine
dc.contributor.departmentGraduate School of Health Sciences
dc.contributor.departmentGraduate School of Sciences and Engineering
dc.contributor.kuauthorCingöz, Ahmet
dc.contributor.kuauthorGümüş, Zeynep Hülya
dc.contributor.kuauthorMorova, Tunç
dc.contributor.kuauthorÖnder, Tuğba Bağcı
dc.contributor.kuauthorÖzyerli, Ezgi
dc.contributor.kuauthorŞeker-Polat, Fidan
dc.contributor.kuauthorSolaroğlu, İhsan
dc.contributor.schoolcollegeinstituteGRADUATE SCHOOL OF HEALTH SCIENCES
dc.contributor.schoolcollegeinstituteGRADUATE SCHOOL OF SCIENCES AND ENGINEERING
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2024-11-09T22:49:39Z
dc.date.issued2021
dc.description.abstractTumor 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.indexedbyWOS
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.issue18
dc.description.openaccessNO
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuN/A
dc.description.sponsorshipScientific and Technological Research Council of Turkey (TUBITAK) [3501]
dc.description.sponsorshipMarie Curie FP7 Career Reintegration Grant (EC) [618673]
dc.description.sponsorshipBAGEP
dc.description.sponsorshipNIH/NCI [U24 CA210993]
dc.description.sponsorshipIcahn Institute
dc.description.sponsorshipNIH [R01CA201148]
dc.description.sponsorshipPresidency 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.volume40
dc.identifier.doi10.1038/s41388-021-01697-6
dc.identifier.eissn1476-5594
dc.identifier.issn0950-9232
dc.identifier.scopus2-s2.0-85103166221
dc.identifier.urihttps://doi.org/10.1038/s41388-021-01697-6
dc.identifier.urihttps://hdl.handle.net/20.500.14288/6543
dc.identifier.wos632820300004
dc.language.isoeng
dc.publisherSpringernature
dc.relation.ispartofoncogene
dc.subjectBiochemistry
dc.subjectMolecular biology
dc.subjectOncology
dc.subjectCell biology
dc.subjectGenetics
dc.subjectHeredity
dc.titleGeneration of TRAIL-resistant cell line models reveals distinct adaptive mechanisms for acquired resistance and re-sensitization
dc.typeJournal Article
dspace.entity.typePublication
local.contributor.kuauthorCingöz, Ahmet
local.contributor.kuauthorÖzyerli, Ezgi
local.contributor.kuauthorMorova, Tunç
local.contributor.kuauthorŞeker-Polat, Fidan
local.contributor.kuauthorGümüş, Zeynep Hülya
local.contributor.kuauthorSolaroğlu, İhsan
local.contributor.kuauthorÖnder, Tuğba Bağcı
local.publication.orgunit1GRADUATE SCHOOL OF HEALTH SCIENCES
local.publication.orgunit1GRADUATE SCHOOL OF SCIENCES AND ENGINEERING
local.publication.orgunit1SCHOOL OF MEDICINE
local.publication.orgunit2School of Medicine
local.publication.orgunit2Graduate School of Health Sciences
local.publication.orgunit2Graduate School of Sciences and Engineering
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