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Updated: Jan 21, 2026
Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids
Published on: December 23, 2022
Targeting inhibitors of apoptosis in oral squamous cell carcinoma in vitro
Mario J J Scheurer1, Axel Seher1, Valentin Steinacker1
1Department of Oral and Maxillofacial Plastic Surgery (Head: A. C. Kübler), University Hospital Würzburg, Pleicherwall 2, 97070 Würzburg, Germany.
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.
Insights
Head and neck cancers resist cell death due to inhibitor of apoptosis proteins (IAPs). The SMAC mimetic LCL161 sensitizes cancer cells to apoptosis, particularly when combined with Fas ligand, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Head and neck cancers, often originating in oral mucosa, are a global health concern.
- Cancer cells frequently overexpress inhibitor of apoptosis proteins (IAPs), conferring resistance to programmed cell death.
- Second mitochondria-derived activator of caspases (SMAC) antagonizes IAPs, promoting apoptosis.
Purpose of the Study:
- To investigate the efficacy of the SMAC mimetic LCL161 in sensitizing oral squamous cell carcinoma (OSCC) cells to apoptosis.
- To evaluate the combined effects of LCL161 and Fas ligand (FasL) on cancer cell death.
- To determine the mechanism of cell death induced by LCL161.
Main Methods:
- Analyzed Fas receptor (FasR) expression using flow cytometry across six OSCC cell lines.
- Treated cell lines with FasL and LCL161, alone and in combination, assessing cytotoxicity via crystal violet assays.
- Utilized Annexin V assays and cell viability assays with specific inhibitors (zVAD-fmk, Necrostatin-1) to characterize cell death pathways.
Main Results:
- LCL161 significantly sensitized four of six OSCC cell lines to FasL-induced apoptosis (p < 0.05), with synergistic effects observed.
- The resistant SCC-25 cell line showed enhanced sensitivity to FasL upon LCL161 treatment.
- LCL161 demonstrated both apoptosis-sensitizing and apoptosis-inducing properties, with induced apoptosis being resistant to inhibition by zVAD-fmk and Nec-1.
Conclusions:
- LCL161 effectively sensitizes oral squamous cell carcinoma cells to apoptosis, especially in combination with FasL.
- Targeting IAPs with SMAC mimetics like LCL161 represents a promising therapeutic strategy for head and neck cancers.
- The proapoptotic potential of LCL161 is significant and warrants further investigation in clinical settings.
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