Ceramide kinase confers tamoxifen resistance in estrogen receptor-positive breast cancer by altering sphingolipid metabolism. (January 2023)

• Record Type: Journal Article
• Authors: Huang, Cheng; Su, Liangping; Chen, Yitian; Wu, Sangqing; Sun, Ruipu; Xu, Qiuping; Qiu, Xiaoyi; Yang, Ciqiu; Kong, Xiangzhan; Qin, Hongquan; Zhao, Xinbao; Jiang, Xue; Wang, Kun; Zhu, Yinghua; Wong, Ping-Pui
• Is Part Of: Pharmacological research. Volume 187(2023)
• Publication Date: 2023-01
• Subjects: ER Estrogen receptor -- WT Wild type -- TAMR Tamoxifen resistance -- SERM Selective estrogen receptor modifiers -- CERK Ceramide kinase -- UGCG UDP-Glucose ceramide glucosyltransferase -- SPHK2 Sphingosine kinase 2 -- SMPD2 Sphingomyelin phosphodiesterase 2 -- CERS3 Ceramide synthase 3 -- SPTLC2 Serine palmitoyltransferase long chain base subunit 2 -- GBA2 Glucosylceramidase beta 2 -- KEGG Kyoto encyclopedia of genes and genomes -- RT-PCR Real time-polymerase chain reaction -- EHF ETS homologous factor -- NSC Non-silencing control -- ChIP Chromatin immunoprecipitation -- IHC Immunohistochemistry; Breast cancer -- Sphingolipid metabolism -- Tamoxifen resistance -- CERK; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106558
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Dysregulated sphingolipid metabolism contributes to ER+ breast cancer progression and therapeutic response, whereas its underlying mechanism and contribution to tamoxifen resistance (TAMR) is unknown. Here, we establish sphingolipid metabolic enzyme CERK as a regulator of TAMR in breast cancer. Multi-omics analysis reveals an elevated CERK driven sphingolipid metabolic reprogramming in TAMR cells, while high CERK expression associates with worse patient prognosis in ER+ breast cancer. CERK overexpression confers tamoxifen resistance and promotes tumorigenicity in ER+ breast cancer cells. Knocking out CERK inhibits the orthotopic breast tumor growth of TAMR cells while rescuing their tamoxifen sensitivity. Mechanistically, the elevated EHF expression transcriptionally up-regulates CERK expression to prohibit tamoxifen-induced sphingolipid ceramide accumulation, which then inhibits tamoxifen-mediated repression on PI3K/AKT dependent cell proliferation and its driven p53/caspase-3 mediated apoptosis in TAMR cells. This work provides insight into the regulation of sphingolipid metabolism in tamoxifen resistance and identifies a potential therapeutic target for this disease. Graphical Abstract: ga1 Highlights: Sphingolipid metabolism is dysregulated in TAMR breast cancer cells, and that is controlled by CERK expression. CERK expression confers TAMR and determines tumorigenicity in ER+ breast cancer cells. TAMR cells up-regulate EHF/CERK mediated sphingolipid metabolic reprogramming to prohibit TAM-induced ceramide accumulation. High CERK/EHF expression correlates with poor prognosis in ER+ breast cancer patients who received endocrine therapy. Knocking out CERK expression reduces the growth of TAMR tumors while rescuing their response to tamoxifen.