Induction of ER and mitochondrial stress by the alkylphosphocholine erufosine in oral squamous cell carcinoma cells
| Autor: | Doaa M. Ali, Himanshu Soni, Hansjörg Eibl, Björn Tews, Martin R. Berger, Ashwini Kumar Sharma, Rainer König, Shariq S. Ansari |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research XBP1 Phosphorylcholine Immunology Antineoplastic Agents Apoptosis Vacuole Endoplasmic Reticulum Article 03 medical and health sciences Cellular and Molecular Neuroscience Cell Line Tumor Autophagy Humans Annexin A5 lcsh:QH573-671 Caspase Membrane Potential Mitochondrial Gene knockdown biology Chemistry lcsh:Cytology Endoplasmic reticulum Cell Biology Endoplasmic Reticulum Stress Organophosphates Mitochondria Quaternary Ammonium Compounds 030104 developmental biology biology.protein Cancer research Unfolded protein response Carcinoma Squamous Cell Calcium Mouth Neoplasms Microtubule-Associated Proteins |
| Zdroj: | Cell Death and Disease, Vol 9, Iss 3, Pp 1-15 (2018) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Endoplasmic reticulum (ER) plays an essential role in cell function and survival. Accumulation of unfolded or misfolded proteins in the lumen of the ER activates the unfolded protein response (UPR), resulting in ER stress and subsequent apoptosis. The alkylphosphocholine erufosine is a known Akt-mTOR inhibitor in oral squamous cell carcinoma (OSCC). In the present study, we evaluate erufosine’s role to induce ER and mitochondrial stress leading to autophagy, apoptosis, and ROS induction. The cellular toxicity of erufosine was determined in two OSCC cell lines and gene expression and enrichment analyses were performed. A positive enrichment of ER stress upon erufosine exposure was observed, which was verified at protein levels for the ER stress sensors and their downstream mediators. Knockdown and pharmacological inhibition of the ER stress sensors PERK and XBP1 revealed their involvement into erufosine’s cellular effects, including proliferation, apoptosis, and autophagy induction. Autophagy was confirmed by increased acidic vacuoles and LC3-B levels. Upon erufosine exposure, calcium influx into the cytoplasm of the two OSCC cell lines was seen. Apoptosis was confirmed by nuclear staining, Annexin-V, and immunoblotting of caspases. The induction of mitochondrial stress upon erufosine exposure was predicted by gene set enrichment analysis (GSEA) and shown by erufosine’s effect on mitochondrial membrane potential, ATP, and ROS production in OSCC cells. These data show that ER and mitochondrial targeting by erufosine represents a new facet of its mechanism of action as well as a promising new framework in the treatment of head and neck cancers. |
| Databáze: | OpenAIRE |
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