Targeting inhibitors of apoptosis in oral squamous cell carcinoma in vitro |
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| Institution: | 1. Department of Oral and Maxillofacial Plastic Surgery (Head: A. C. Kübler), University Hospital Würzburg, Pleicherwall 2, 97070 Würzburg, Germany;2. Interdisciplinary Center for Clinical Research (Head: M. Goebeler), University Hospital Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany;3. Comprehensive Cancer Center Mainfranken (CCC MF) (Head: R. C. Bargou), Josef-Schneider-Str. 6, 97080 Würzburg, Germany;1. Hospital Villa dei Pini, Department of Surgery, Section of Maxillofacial Surgery, Civitanova Marche, MC, Italy;2. Department of Oral and Maxillofacial Surgery & Pathology, University of Mississippi Medical Center, Jackson, MS, USA;3. Department of Medicine and Surgery, University of Salerno, Salerno, Italy;4. Department of Medicine and Surgery, Unit of Maxillofacial Surgery, University of Salerno, Salerno, Italy;1. Department of Oral and Maxillofacial Surgery, Friedrich-Alexander-University Erlangen-Nuremberg, Glueckstrasse 11, 91054 Erlangen, Germany;2. Department of Oral and Maxillofacial Surgery, Technical University of Munich, Ismaninger Strasse 22, 81675 Munich, Germany;3. Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of Oral and Maxillofacial Surgery, Germany;1. Division of Plastic and Reconstructive Surgery, Department of Surgery, Faculty of Medicine, Chiang Mai University, Thailand;2. Department of Radiology, Faculty of Medicine, Chiang Mai University, Thailand |
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| Abstract: | Head and neck cancer, which predominantly arises from the oral mucosa, represents the sixth most common malignancy worldwide. These cancer cells can be resistant to programmed cell death triggered by extrinsic stimuli due to innate overexpression of inhibitor of apoptosis proteins (IAPs). The cellular protein second mitochondria-derived activator of caspases (SMAC) can antagonize IAP-induced caspase inhibition and thus trigger apoptosis. Here, we investigate the cell death-sensitizing effects of the SMAC mimetic LCL161 alone and in combination with Fas ligand (FasL) using a panel of six cell lines. Fas receptor (FasR) expression was analyzed by flow cytometry. Cells were treated with FasL and LCL161 alone or in combination, and cytotoxicity was measured using crystal violet assays. Annexin V and cell viability assays using zVAD-fmk and Necrostatin-1 (Nec-1) were carried out to assess the type of programmed cell death induced by LCL161. To demonstrate the sensitizing effects of LCL161, we employed the t-test to compare the effects of FasL alone and in combination with LCL161. Linear regression analysis was performed to determine initial and half maximal inhibitory concentrations (IC10 and IC50, respectively). Distinct FasR expression was detected in each cell line. Four of six cell lines were significantly sensitized to FasL by LCL161 (p < 0.05), and synergistic effects were observed (y < 1). Moreover, the initially resistant cell line SCC-25 was effectively sensitized to FasL by LCL161. Annexin V FACS analysis demonstrated apoptosis-sensitizing and apoptosis-inducing effects of LCL161 across all cell lines. Using specific cell death inhibitors (zVAD-fmk and Nec-1), we demonstrated that LCL161-initiated apoptosis could not be prevented, highlighting the proapoptotic potential of this mimetic in these cells. Our findings show the effectiveness of apoptotic sensitization of OSCC cells by LCL161 in combination with FasL, thus confirming the importance of an IAP-targeting therapeutic approach for oral squamous cell carcinoma. |
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| Keywords: | LCL161 Oral squamous cell carcinoma Inhibitor of apoptosis proteins SMAC mimetics FasL Apoptosis |
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