{"doi":"10.14740/wjon1890","title":"Targeting SNAI1-Mediated Colorectal Cancer Chemoresistance and Stemness by Sphingosine Kinase 2 Inhibition","abstract":"Background: Epithelial-to-mesenchymal transition (EMT), cancer stem cells (CSCs), and colorectal cancer (CRC) therapy resistance are closely associated. Prior reports have demonstrated that sphingosine-1-phosphate (S1P) supports stem cells and maintains the CSC phenotype. We hypothesized that the EMT inducer SNAI1 drives S1P signaling to amplify CSC self-renewal capacity and chemoresistance. Methods: CRC cell lines with or without ectopic expression of SNAI1 were used to study the role of S1P signaling as mediators of cancer stemness and 5-fluorouracil (5FU) chemoresistance. The therapeutic ability of sphingosine kinase 2 (SPHK2) was assessed using siRNA and ABC294640, a SPHK2 inhibitor. CSCs were isolated from patient-derived xenografts (PDXs) and assessed for SPHK2 and SNAI1 expression. Results: self-renewal and sensitized cells to 5FU. CSCs isolated from CRC PDXs express increased SPHK2 relative to the non-CSC population. Combination ABC294640/5FU therapy significantly inhibited tumor growth in mice and enhanced 5FU response in therapy-resistant CRC patient-derived tumor organoids (PDTOs). Conclusions: SNAI1/SPHK2 signaling mediates cancer stemness and 5FU resistance, implicating S1P as a therapeutic target for CRC. The S1P inhibitor ABC294640 holds potential as a therapeutic agent to target CSCs in therapy refractory CRC.","journal":"World Journal of Oncology","year":2024,"id":458429,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9604,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1284718,"name":"Zachary Gao","orcid":null,"position":1,"is_corresponding":false},{"id":225922,"name":"Yun Zhu","orcid":"0000-0003-3531-3544","position":2,"is_corresponding":false},{"id":1284287,"name":"Jiangling Dong","orcid":"0000-0001-9742-2469","position":3,"is_corresponding":false},{"id":469158,"name":"Scott A. Becker","orcid":"0000-0003-0194-4874","position":4,"is_corresponding":false},{"id":1284719,"name":"Alhaji Janneh","orcid":null,"position":5,"is_corresponding":false},{"id":593575,"name":"Besim Öğretmen","orcid":"0000-0002-1019-5660","position":6,"is_corresponding":false},{"id":469162,"name":"E. Ramsay Camp","orcid":"0000-0003-0005-7536","position":7,"is_corresponding":false},{"id":469157,"name":"Harinarayanan Janakiraman","orcid":"0000-0002-3043-2352","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T02:03:46.117860Z","pmid":"39328328","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}