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Published on: December 9, 2016
Transcriptome‑based drug repositioning identifies TPCA‑1 as a potential selective inhibitor of esophagus squamous
Zongyang Li1, Linjun Zou1, Zhi-Xiong Xiao1
1Center of Growth, Metabolism and Aging, Key Laboratory of Bio‑Resources and Eco‑Environment, College of Life Sciences, Sichuan University, Chengdu, Sichuan 610064, P.R. China.
Abstract:
Esophageal squamous cell carcinoma (ESCC) is a cancer type with limited treatment options. The present study aimed to screen for small molecules that may inhibit ESCC cell viability. The small‑molecule‑perturbed signatures were extrapolated from the library of integrated network‑based cellular signatures (LINCS) database. Since LINCS does not include small‑molecule‑perturbed signatures of ESCC cells, it was hypothesized that non‑ESCC cell lines that display transcriptome profiles similar to those of ESCC may have similar small‑molecule‑perturbated responses to ESCC cells and that identifying small molecules that inhibit the viability of these non‑ESCC cells may also inhibit the viability of ESCC cells. The transcriptomes of >1,000 cancer cell lines from the Cancer Cell Line Encyclopedia database were analyzed and 70 non‑ESCC cell lines exhibiting similar transcriptome profiles to those of ESCC cells were identified. Among them, six cell lines with transcriptome signatures upon drug perturbation were available in the LINCS, which were used as reference signatures. A total of 20 ESCC datasets were analyzed and 522 downregulated and 461 upregulated differentially expressed genes (DEGs) that were consistently altered across >50% of the datasets were identified. These DEGs together with the reference signatures were then used as inputs of the ZhangScore method to score small molecules that may reverse transcriptome alterations of ESCC. Among the top‑ranked 50 molecules identified by the ZhangScore, four candidates that may inhibit ESCC cell viability were experimentally verified. Furthermore, 2‑[(aminocarbonyl)amino]‑5‑(4‑fluorophenyl)‑3‑-thiophenecarboxamide (TPCA‑1), an inhibitor of the NF‑κB pathway, was able to preferentially inhibit the viability of ESCC cells compared with non‑tumorigenic epithelial Het‑1A cells. Mechanistically, TPCA‑1 induced ESCC KYSE‑450 cell apoptosis by inhibiting the phosphorylation of inhibitor of NF‑κB kinase subunit β, leading to IκBα stabilization and NF‑κB signaling pathway inhibition. Collectively, these results demonstrated that LINCS‑based drug repositioning may facilitate drug discovery and that TPCA‑1 may be a promising candidate molecule in the treatment of ESCC.
Insights
Researchers identified potential new treatments for esophageal squamous cell carcinoma (ESCC) by screening small molecules. A novel compound, TPCA-1, effectively inhibited ESCC cell growth by targeting the NF-κB pathway.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Esophageal squamous cell carcinoma (ESCC) presents limited therapeutic options.
- Drug repositioning strategies are crucial for identifying novel cancer treatments.
- The Library of Integrated Network-Based Cellular Signatures (LINCS) database offers valuable drug perturbation data.
Purpose of the Study:
- To screen for small molecules that inhibit esophageal squamous cell carcinoma (ESCC) cell viability.
- To leverage the LINCS database for drug discovery in ESCC.
- To identify and validate novel therapeutic candidates for ESCC treatment.
Main Methods:
- Transcriptome analysis of >1,000 cancer cell lines to identify ESCC-like non-ESCC cell lines.
- Utilized the ZhangScore method with LINCS database signatures and differentially expressed genes (DEGs) from ESCC datasets.
- Experimental validation of top-ranked small molecules, including mechanistic studies of TPCA-1.
Main Results:
- Identified 70 non-ESCC cell lines with transcriptome profiles similar to ESCC.
- Screened 50 small molecules, identifying four candidates that inhibit ESCC cell viability.
- TPCA-1, an NF-κB pathway inhibitor, preferentially inhibited ESCC cell viability and induced apoptosis.
Conclusions:
- LINCS-based drug repositioning is a viable strategy for ESCC drug discovery.
- TPCA-1 demonstrates significant potential as a therapeutic agent for esophageal squamous cell carcinoma.
- Targeting the NF-κB pathway offers a promising therapeutic approach for ESCC.
