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Unfolded Protein Response as a Therapeutic Target: 4-(Heptyloxy)phenol Induces Programmed Cell Death in Ewing Sarcoma
Nenggang Zhang1, Mary Perez1, Gaye N Jenkins1
1Texas Children's Cancer Center, Department of Pediatrics, Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
Abstract:
Ewing sarcoma is a rare and aggressive pediatric malignancy with limited therapeutic options, particularly for relapsed or refractory cases, highlighting the urgent need for innovative treatment strategies. In this study, we identify endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) as critical therapeutic vulnerabilities in Ewing sarcoma and introduce 4-(heptyloxy)phenol (AC-45594) as a novel small-molecule agent that exploits these stress pathways. AC-45594 selectively inhibited the growth of Ewing sarcoma cells among 13 cancer and 6 noncancerous cell lines, demonstrating marked tumor specificity. Structure-activity relationship studies revealed that both the phenolic hydroxyl group and an optimal alkoxy chain length (7-9 carbon atoms) are essential for its activity. Mechanistically, AC-45594 induces ERS, activates UPR, and drives a shift from adaptive to terminal stress signaling, culminating in apoptosis of Ewing sarcoma cells. Proteomic and gene expression analyses further supported the selective activation of proapoptotic UPR signaling. These findings establish ERS and UPR as actionable targets in Ewing sarcoma and position AC-45594 as a first-in-class compound capable of selectively inducing stress-driven cell death. This work lays the foundation for a new class of therapeutics targeting maladaptive stress responses in pediatric sarcomas and potentially other hard-to-treat cancers.
Insights
Researchers identified endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) as vulnerabilities in Ewing sarcoma (ES). A novel compound, AC-45594, selectively targets these pathways, inducing cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ewing sarcoma (ES) is an aggressive pediatric cancer with limited treatment options for relapsed or refractory disease.
- There is a critical need for novel therapeutic strategies targeting the underlying biology of ES.
Purpose of the Study:
- To identify therapeutic vulnerabilities in ES related to cellular stress pathways.
- To introduce and characterize a novel small-molecule agent, AC-45594, targeting these vulnerabilities.
Main Methods:
- Screening of cell lines to identify AC-45594's selective activity.
- Structure-activity relationship studies to determine essential chemical features of AC-45594.
- Mechanistic studies involving proteomic and gene expression analyses to elucidate the mode of action.
Main Results:
- AC-45594 demonstrated selective inhibition of ES cell growth across multiple cell lines.
- The compound's activity is dependent on its phenolic hydroxyl group and a 7-9 carbon alkoxy chain.
- AC-45594 induces endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR), shifting signaling towards apoptosis in ES cells.
Conclusions:
- Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are actionable therapeutic targets in Ewing sarcoma (ES).
- AC-45594 represents a first-in-class agent that selectively induces stress-driven apoptosis in ES.
- This research provides a foundation for developing new therapeutics targeting stress responses in pediatric sarcomas and other cancers.
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