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Keywords = SORE6-GFP reporter system

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19 pages, 3083 KB  
Article
High-Throughput Drug Screening Revealed That Ciclopirox Olamine Can Engender Gastric Cancer Stem-like Cells
by Diana Pádua, Paula Figueira, Mariana Pinto, André Filipe Maia, Joana Peixoto, Raquel T. Lima, António Pombinho, Carlos Filipe Pereira, Raquel Almeida and Patrícia Mesquita
Cancers 2023, 15(17), 4406; https://doi.org/10.3390/cancers15174406 - 3 Sep 2023
Cited by 2 | Viewed by 3582
Abstract
Cancer stem cells (CSCs) are relevant therapeutic targets for cancer treatment. Still, the molecular circuits behind CSC characteristics are not fully understood. The low number of CSCs can sometimes be an obstacle to carrying out assays that explore their properties. Thus, increasing CSC [...] Read more.
Cancer stem cells (CSCs) are relevant therapeutic targets for cancer treatment. Still, the molecular circuits behind CSC characteristics are not fully understood. The low number of CSCs can sometimes be an obstacle to carrying out assays that explore their properties. Thus, increasing CSC numbers via small molecule-mediated cellular reprogramming appears to be a valid alternative tool. Using the SORE6-GFP reporter system embedded in gastric non-CSCs (SORE6−), we performed a high-throughput image-based drug screen with 1200 small molecules to identify compounds capable of converting SORE6− to SORE6+ (CSCs). Here, we report that the antifungal agent ciclopirox olamine (CPX), a potential candidate for drug repurposing in cancer treatment, is able to reprogram gastric non-CSCs into cancer stem-like cells via activation of SOX2 expression and increased expression of C-MYC, HIF-1α, KLF4, and HMGA1. This reprogramming depends on the CPX concentration and treatment duration. CPX can also induce cellular senescence and the metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis. We also disclose that the mechanism underlying the cellular reprogramming is similar to that of cobalt chloride (CoCl2), a hypoxia-mimetic agent. Full article
(This article belongs to the Section Cancer Drug Development)
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20 pages, 3758 KB  
Article
A SOX2 Reporter System Identifies Gastric Cancer Stem-Like Cells Sensitive to Monensin
by Diana Pádua, Rita Barros, Ana Luísa Amaral, Patrícia Mesquita, Ana Filipa Freire, Mafalda Sousa, André Filipe Maia, Inês Caiado, Hugo Fernandes, António Pombinho, Carlos Filipe Pereira and Raquel Almeida
Cancers 2020, 12(2), 495; https://doi.org/10.3390/cancers12020495 - 20 Feb 2020
Cited by 43 | Viewed by 7785
Abstract
Gastric cancer remains a serious health burden with few therapeutic options. Therefore, the recognition of cancer stem cells (CSCs) as seeds of the tumorigenic process makes them a prime therapeutic target. Knowing that the transcription factors SOX2 and OCT4 promote stemness, our approach [...] Read more.
Gastric cancer remains a serious health burden with few therapeutic options. Therefore, the recognition of cancer stem cells (CSCs) as seeds of the tumorigenic process makes them a prime therapeutic target. Knowing that the transcription factors SOX2 and OCT4 promote stemness, our approach was to isolate stem-like cells in human gastric cancer cell lines using a traceable reporter system based on SOX2/OCT4 activity (SORE6-GFP). Cells transduced with the SORE6-GFP reporter system were sorted into SORE6+ and SORE6– cell populations, and their biological behavior characterized. SORE6+ cells were enriched for SOX2 and exhibited CSC features, including a greater ability to proliferate and form gastrospheres in non-adherent conditions, a larger in vivo tumor initiating capability, and increased resistance to 5-fluorouracil (5-FU) treatment. The overexpression and knockdown of SOX2 revealed a crucial role of SOX2 in cell proliferation and drug resistance. By combining the reporter system with a high-throughput screening of pharmacologically active small molecules we identified monensin, an ionophore antibiotic, displaying selective toxicity to SORE6+ cells. The ability of SORE6-GFP reporter system to recognize cancer stem-like cells facilitates our understanding of gastric CSC biology and serves as a platform for the identification of powerful therapeutics for targeting gastric CSCs. Full article
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