Bozkurt, Emir
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Bozkurt, E.
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Email Address
emrbzkrt@gmail.com
Main Affiliation
05.08. Genetics and Bioengineering
Status
Former Staff
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Sustainable Development Goals
Documents
21
Citations
530
h-index
13
Documents
35
Citations
475
Scholarly Output
3
Articles
3
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0/0
Supervised MSc Theses
0
Supervised PhD Theses
0
WoS Citation Count
97
Scopus Citation Count
103
WoS h-index
3
Scopus h-index
3
Patents
0
Projects
0
WoS Citations per Publication
32.33
Scopus Citations per Publication
34.33
Open Access Source
3
Supervised Theses
0
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3 results
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Article Citation - WoS: 29Citation - Scopus: 29TRAIL signaling promotes entosis in colorectal cancer(Rockefeller Univ Press, 2021) Bozkurt, Emir; Dussmann, Heiko; Salvucci, Manuela; Cavanagh, Brenton L.; Van Schaeybroeck, Sandra; Longley, Daniel B.; Martin, Seamus J.Bozkurt et al. find that besides activating apoptosis, TRAIL signaling induces entosis in colon cancer cells through TRAIL receptors and structural presence but not catalytic activity of caspase-8. Moreover, they provide evidence for an association of TRAIL signaling, cell-in-cell structures, and clinical outcome in CRC. Entosis is a form of nonphagocytic cell-in-cell (CIC) interaction where a living cell enters into another. Tumors show evidence of entosis; however, factors controlling entosis remain to be elucidated. Here, we find that besides inducing apoptosis, TRAIL signaling is a potent activator of entosis in colon cancer cells. Initiation of both apoptosis and entosis requires TRAIL receptors DR4 and DR5; however, induction of apoptosis and entosis diverges at caspase-8 as its structural presence is sufficient for induction of entosis but not apoptosis. Although apoptosis and entosis are morphologically and biochemically distinct, knockout of Bax and Bak, or inhibition of caspases, also inhibits entotic cell death and promotes survival and release of inner cells. Analysis of colorectal cancer tumors reveals a significant association between TRAIL signaling and CIC structures. Finally, the presence of CIC structures in the invasive front regions of colorectal tumors shows a strong correlation with adverse patient prognosis.Article Citation - WoS: 23Citation - Scopus: 23Molecular Subtype-Specific Responses of Colon Cancer Cells To the Smac Mimetic Birinapant(Springernature, 2020) Fichtner, Michael; Bozkurt, Emir; Salvucci, Manuela; McCann, Christopher; McAllister, Katherine A.; Halang, Luise; Duessmann, HeikoColorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP. Due to the multiple molecular mechanisms-of-action of these targets, responses to IAP antagonist may differ between molecularly distinct colon cancer cells. In this study, responses to the IAP antagonist Birinapant and oxaliplatin/5-fluorouracil (5-FU) were investigated in 14 colon cancer cell lines, representing the consensus molecular subtypes (CMS). Treatment with Birinapant alone did not result in a substantial increase in apoptotic cells in this cell line panel. Annexin-V/PI assays quantified by flow cytometry and high-content screening showed that Birinapant increased responses of CMS1 and partially CMS3 cell lines to oxaliplatin/5-FU, whereas CMS2 cells were not effectively sensitized. FRET-based imaging of caspase-8 and -3 activation validated these differences at the single-cell level, with CMS1 cells displaying sustained activation of caspase-8-like activity during Birinapant and oxaliplatin/5-FU co-treatment, ultimately activating the intrinsic mitochondrial apoptosis pathway. In CMS2 cell lines, Birinapant exhibited synergistic effects in combination with TNF alpha, suggesting that Birinapant can restore extrinsic apoptosis signaling in the context of inflammatory signals in this subtype. To explore this further, we co-cultured CMS2 and CMS1 colon cancer cells with peripheral blood mononuclear cells. We observed increased cell death during Birinapant single treatment in these co-cultures, which was abrogated by anti-TNF alpha -neutralizing antibodies. Collectively, our study demonstrates that IAP inhibition is a promising modulator of response to oxaliplatin/5-FU in colorectal cancers of the CMS1 subtype, and may show promise as in the CMS2 subtype, suggesting that molecular subtyping may aid as a patient stratification tool for IAP antagonists in this disease.Article Citation - WoS: 45Citation - Scopus: 51Development of Epha2 Sirna-Loaded Lipid Nanoparticles and Combination With a Small-Molecule Histone Demethylase Inhibitor in Prostate Cancer Cells and Tumor Spheroids(Bmc, 2021) Oner, Ezgi; Kotmakci, Mustafa; Baird, Anne-Marie; Gray, Steven G.; Debelec Butuner, Bilge; Bozkurt, Emir; Kantarci, Ayse GultenBackground: siRNAs hold a great potential for cancer therapy, however, poor stability in body fluids and low cellular uptake limit their use in the clinic. To enhance the bioavailability of siRNAs in tumors, novel, safe, and effective carriers are needed. Results: Here, we developed cationic solid lipid nanoparticles (cSLNs) to carry siRNAs targeting EphA2 receptor tyrosine kinase (siEphA2), which is overexpressed in many solid tumors including prostate cancer. Using DDAB cationic lipid instead of DOTMA reduced nanoparticle size and enhanced both cellular uptake and gene silencing in prostate cancer cells. DDAB-cSLN showed better cellular uptake efficiency with similar silencing compared to commercial transfection reagent (Dharmafect 2). After verifying the efficacy of siEphA2-loaded nanoparticles, we further evaluated a potential combination with a histone lysine demethylase inhibitor, JIB-04. Silencing EphA2 by siEphA2-loaded DDAB-cSLN did not affect the viability (2D or 3D culture), migration, nor clonogenicity of PC-3 cells alone. However, upon co-administration with JIB-04, there was a decrease in cellular responses. Furthermore, JIB-04 decreased EphA2 expression, and thus, silencing by siEphA2-loaded nanoparticles was further increased with co-treatment. Conclusions: We have successfully developed a novel siRNA-loaded lipid nanoparticle for targeting EphA2. Moreover, preliminary results of the effects of JIB-04, alone and in combination with siEphA2, on prostate cancer cells and prostate cancer tumor spheroids were presented for the first time. Our delivery system provides high transfection efficiency and shows great promise for targeting other genes and cancer types in further in vitro and in vivo studies.