Ceramide kinase confers tamoxifen resistance in estrogen receptor-positive breast cancer by altering sphingolipid metabolism
Ceramide kinase confers tamoxifen resistance in estrogen receptor-positive breast cancer by altering sphingolipid metabolism
复制标题
神经酰胺激酶通过改变鞘脂代谢赋予雌激素受体阳性乳腺癌他莫昔芬耐药性
DOI：
10.1016/j.phrs.2022.106558
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发表时间：
2022-11-24
影响因子：
9.3
通讯作者：
Wong, Ping-Pui
中科院分区：
文献类型：
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作者：
Huang, Cheng;Su, Liangping;Wong, Ping-Pui
鞘脂代谢失调有助于ER+乳腺癌进展和治疗反应，而其潜在机制和对他莫昔芬耐药（TAMR）的贡献尚不清楚。在这里，我们建立了鞘脂代谢酶CERK作为乳腺癌TAMR的调节剂。多组学分析揭示了TAMR细胞中升高的CERK驱动的鞘脂代谢重编程，而高CERK表达与ER+乳腺癌中更差的患者预后相关。在ER+乳腺癌细胞中，CERK过表达赋予他莫昔芬抗性并促进致瘤性。敲除CERK抑制了TAMR细胞的原位乳腺肿瘤生长，同时挽救了它们对他莫昔芬的敏感性。从机制上讲，EHF表达的升高在转录上上调CERK表达，以阻止他莫昔芬诱导的鞘脂神经酰胺积累，然后抑制他莫昔芬介导的对PI 3 K/AKT依赖性细胞增殖的抑制及其驱动的p53/caspase-3介导的TAMR细胞凋亡。这项工作提供了深入了解他莫昔芬耐药性中鞘脂代谢的调节，并确定了这种疾病的潜在治疗靶点。
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.