PMID- 37885013 OWN - NLM STAT- MEDLINE DCOM- 20231116 LR - 20231116 IS - 1476-511X (Electronic) IS - 1476-511X (Linking) VI - 22 IP - 1 DP - 2023 Oct 26 TI - Ceramide synthase 4 overexpression exerts oncogenic properties in breast cancer. PG - 183 LID - 10.1186/s12944-023-01930-z [doi] LID - 183 AB - BACKGROUND: Ceramide, a bioactive signaling sphingolipid, has long been implicated in cancer. Members of the ceramide synthase (CerS) family determine the acyl chain lengths of ceramides, with ceramide synthase 4 (CerS4) primarily generating C18-C20-ceramide. Although CerS4 is known to be overexpressed in breast cancer, its role in breast cancer pathogenesis is not well established. METHODS: To investigate the role of CerS4 in breast cancer, public datasets, including The Cancer Genome Atlas (TCGA) and two Gene Expression Omnibus (GEO) datasets (GSE115577 and GSE96058) were analyzed. Furthermore, MCF-7 cells stably overexpressing CerS4 (MCF-7/CerS4) as a model for luminal subtype A (LumA) breast cancer were produced, and doxorubicin (also known as Adriamycin [AD])-resistant MCF-7/ADR cells were generated after prolonged treatment of MCF-7 cells with doxorubicin. Kaplan-Meier survival analysis assessed the clinical significance of CERS4 expression, while Student's t-tests or Analysis of Variance (ANOVA) compared gene expression and cell viability in different MCF-7 cell lines. RESULTS: Analysis of the public datasets revealed elevated CERS4 expression in breast cancer, especially in the most common breast cancer subtype, LumA. Persistent CerS4 overexpression in MCF-7 cells activated multiple cancer-associated pathways, including pathways involving sterol regulatory element-binding protein, nuclear factor kappa B (NF-kappaB), Akt/mammalian target of rapamycin (mTOR), and beta-catenin. Furthermore, MCF-7/CerS4 cells acquired doxorubicin, paclitaxel, and tamoxifen resistance, with concomitant upregulation of ATP-binding cassette (ABC) transporter genes, such as ABCB1, ABCC1, ABCC2, ABCC4, and ABCG2. MCF-7/CerS4 cells were characterized by increased cell migration and epithelial-mesenchymal transition (EMT). Finally, CERS4 knockdown in doxorubicin-resistant MCF-7/ADR cells resulted in reduced activation of cancer-associated pathways (NF-kappaB, Akt/mTOR, beta-catenin, and EMT) and diminished chemoresistance, accompanied by ABCB1 and ABCC1 downregulation. CONCLUSIONS: Chronic CerS4 overexpression may exert oncogenic effects in breast cancer via alterations in signaling, EMT, and chemoresistance. Therefore, CerS4 may represent an attractive target for anticancer therapy, especially in LumA breast cancer. CI - (c) 2023. The Author(s). FAU - Kim, Su-Jeong AU - Kim SJ AD - Department of Biochemistry, Chung-Ang University College of Medicine, Heukseok-lo 84, DongJak-gu, Seoul, 06974, Republic of Korea. FAU - Seo, Incheol AU - Seo I AD - Department of Immunology, Kyungpook National University School of Medicine, Daegu, 41944, Republic of Korea. FAU - Kim, Min Hee AU - Kim MH AD - Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, 07804, Republic of Korea. FAU - Park, Joo-Won AU - Park JW AD - Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, 07804, Republic of Korea. FAU - Kim, Shin AU - Kim S AD - Department of Immunology, School of Medicine, Keimyung University, Dalgubeol-daero 1095, Dalseo-gu, Daegu, 42601, Republic of Korea. god98005@dsmc.or.kr. FAU - Park, Woo-Jae AU - Park WJ AD - Department of Biochemistry, Chung-Ang University College of Medicine, Heukseok-lo 84, DongJak-gu, Seoul, 06974, Republic of Korea. ooze@cau.ac.kr. LA - eng GR - NRF-2021R1I1A3A04037479/Korean Government Ministry of Education, Science and Technology/ GR - NRF-2021R1F1A1045565/Korean Government Ministry of Education, Science and Technology/ PT - Journal Article DEP - 20231026 PL - England TA - Lipids Health Dis JT - Lipids in health and disease JID - 101147696 RN - 0 (ATP-Binding Cassette Transporters) RN - 0 (beta Catenin) RN - EC 1.3.1.- (dihydroceramide desaturase) RN - 80168379AG (Doxorubicin) RN - 0 (NF-kappa B) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.3.1.24 (CERS4 protein, human) RN - EC 2.3.1.24 (Sphingosine N-Acyltransferase) SB - IM MH - Female MH - Humans MH - ATP-Binding Cassette Transporters MH - beta Catenin/genetics/metabolism MH - *Breast Neoplasms/pathology MH - Doxorubicin/pharmacology/therapeutic use MH - Drug Resistance, Neoplasm/genetics MH - NF-kappa B/metabolism MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - TOR Serine-Threonine Kinases/metabolism MH - *Sphingosine N-Acyltransferase/genetics MH - MCF-7 Cells PMC - PMC10605224 OTO - NOTNLM OT - Ceramide acyl chain length OT - Ceramide synthase 4 OT - Chemoresistance OT - Epithelial mesenchymal transition OT - Luminal subtype a breast cancer OT - Oncogene COIS- The authors declare that they have no competing interests. EDAT- 2023/10/27 00:43 MHDA- 2023/10/30 06:47 PMCR- 2023/10/26 CRDT- 2023/10/26 23:59 PHST- 2023/06/23 00:00 [received] PHST- 2023/09/19 00:00 [accepted] PHST- 2023/10/30 06:47 [medline] PHST- 2023/10/27 00:43 [pubmed] PHST- 2023/10/26 23:59 [entrez] PHST- 2023/10/26 00:00 [pmc-release] AID - 10.1186/s12944-023-01930-z [pii] AID - 1930 [pii] AID - 10.1186/s12944-023-01930-z [doi] PST - epublish SO - Lipids Health Dis. 2023 Oct 26;22(1):183. doi: 10.1186/s12944-023-01930-z.