Research Project: Glioblastoma Multiform (Gbm) Tümörlerini Trial (TumorNecrosis Factor Related Apoptosis Inducing Ligand)`E Duyarlılığını Etkileyen Faktörlerin Belirlenmesi ve Trail`E Duyarlılığı Arttırıcı Yeni Kimyasalların Bulunması
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Contributors
Funders
ID
TB.00127
Authors
Önder, Tuğba Bağcı
Faculty Member
Publications
The pro-apoptotic Bcl-2 family member Harakiri (HRK) induces cell death in glioblastoma multiforme
(Nature Publishing Group (NPG), 2019) Cingöz, Ahmet; Karahüseyinoğlu, Serçin; Kayabölen, Alişan; Kaya, Ezgi; Lokumcu, Tolga; Önder, Tuğba Bağcı; Şahin, Gizem Nur; Şeker-Polat, Fidan; Şenbabaoğlu, Filiz; Sur, İlknur Erdem; School of Medicine; Yes; SCHOOL OF MEDICINE
Harakiri (HRK) is a BH3-only protein of the Bcl-2 family and regulates apoptosis by interfering with anti-apoptotic Bcl-2 and Bcl-xL proteins. While its function is mainly characterized in the nervous system, its role in tumors is ill-defined with few studies demonstrating HRK silencing in tumors. In this study, we investigated the role of HRK in the most aggressive primary brain tumor, glioblastoma multiforme (GBM). We showed that HRK is differentially expressed among established GBM cell lines and that HRK overexpression can induce apoptosis in GBM cells at different levels. This phenotype can be blocked by forced expression of Bcl-2 and Bcl-xL, suggesting the functional interaction of Bcl-2/ Bcl-xL and HRK in tumor cells. Moreover, HRK overexpression cooperates with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a known tumor-specific pro-apoptotic agent. Besides, secondary agents that augment TRAIL response, such as the histone deacetylase inhibitor MS-275, significantly increases HRK expression. In addition, GBM cell response to TRAIL and MS-275 can be partly abolished by HRK silencing. Finally, we showed that HRK induction suppresses tumor growth in orthotopic GBM models in vivo, leading to increased survival. Taken together, our results suggest that HRK expression is associated with GBM cell apoptosis and increasing HRK activity in GBM tumors might offer new therapeutic approaches.
Generation of TRAIL-resistant cell line models reveals distinct adaptive mechanisms for acquired resistance and re-sensitization
(Springer Nature, 2021) Cingöz, Ahmet; Gümüş, Zeynep Hülya; Morova, Tunç; Önder, Tuğba Bağcı; Özyerli, Ezgi; Şeker-Polat, Fidan; Solaroğlu, İhsan; Esai Selvan, Myvizhi; Bhere, Deepak; Shah, Khalid; School of Medicine; KUTTAM (Koç University Research Center for Translational Medicine); Yes; SCHOOL OF MEDICINE; Research Center
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.
