Notch Signaling Regulates Mitochondrial Metabolism and NF-κB Activity in Triple-Negative Breast Cancer Cells via IKKα-Dependent Non-canonical Pathways
Notch Signaling Regulates Mitochondrial Metabolism and NF-κB Activity in Triple-Negative Breast Cancer Cells via IKKα-Dependent Non-canonical Pathways
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DOI：
10.3389/fonc.2018.00575
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发表时间：
2018-12-04
影响因子：
4.7
通讯作者：
Miele, Lucio
中科院分区：
文献类型：
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作者：
Hossain, Fokhrul;Sorrentino, Claudia;Miele, Lucio
三阴性乳腺癌（TNBC）患者具有较高的复发和转移风险，目前的治疗选择仍然有限。癌症干细胞样细胞（CSCs）与癌症的发生、发展和化疗耐药性有关。Notch信号传导是调节TNBC CSC存活的关键途径。用PI 3 K或mT 0 RC 1/2抑制剂治疗TNBC导致耐药性、Notch依赖性CSC。然而，TNBC CSC中的下游机制和潜在的可药物化Notch效应物在很大程度上是未知的。我们研究了来自代表不同TNBC分子亚型的细胞系以及新的患者来源模型的TNBC CSC中Notch信号传导下游的AKT途径和线粒体代谢的作用。我们证明，TNBC细胞暴露于重组Notch配体Jagged 1导致快速AKT磷酸化的Notch 1依赖，但RBP-JK独立的方式。这需要mTOR和IKK alpha。Jagged 1还以AKT和IKK依赖的方式刺激线粒体呼吸和发酵。Notch 1与TNBC细胞中的线粒体共定位。通过γ分泌酶抑制剂PF-03084014与AKT抑制剂MK-2206或IKK靶向NF-κ B抑制剂Bay 11 -7082组合对Notch切割的药理学抑制，阻断了分选的CD 90（hi）或CD 44 + CD 24（low）（CSC）细胞的次级乳腺球形成。TNBC患者来源的模型给出了相当的结果。除了线粒体氧化代谢，Jagged 1还触发抗凋亡基因cIAP-2的核NF-κ B依赖性转录。这需要Notch 1、IKK α和NE-κ B募集到cIAP-2启动子。我们的观察结果支持一个模型，其中Jagged 1触发IKK α依赖性，线粒体和核Notch 1信号，刺激PTEN野生型TNBC细胞中AKT磷酸化，氧化代谢和存活基因的转录。这些数据表明，靶向Notch、AKT和NE-κ B途径的交叉的组合治疗具有针对具有Notch 1和野生型PTEN表达的TNBC病例中的CSC的潜在治疗应用。
Triple negative breast cancer (TNBC) patients have high risk of recurrence and metastasis, and current treatment options remain limited. Cancer stem-like cells (CSCs) have been linked to cancer initiation, progression and chemotherapy resistance. Notch signaling is a key pathway regulating TNBC CSC survival. Treatment of TNBC with PI3K or mTORC1/2 inhibitors results in drug-resistant, Notch-dependent CSC. However, downstream mechanisms and potentially druggable Notch effectors in TNBC CSCs are largely unknown. We studied the role of the AKT pathway and mitochondrial metabolism downstream of Notch signaling in TNBC CSC from cell lines representative of different TNBC molecular subtypes as well as a novel patient-derived model. We demonstrate that exposure of TNBC cells to recombinant Notch ligand Jagged1 leads to rapid AKT phosphorylation in a Notch1-dependent but RBP-JK independent fashion. This requires mTOR and IKK alpha. Jagged1 also stimulates mitochondrial respiration and fermentation in an AKT- and IKK-dependent fashion. Notch1 co-localizes with mitochondria in TNBC cells. Pharmacological inhibition of Notch cleavage by gamma secretase inhibitor PF-03084014 in combination with AKT inhibitor MK-2206 or IKK-targeted NF-kappa B inhibitor Bay11-7082 blocks secondary mammosphere formation from sorted CD90(hi) or CD44+CD24(low) (CSCs) cells. A TNBC patient-derived model gave comparable results. Besides mitochondrial oxidative metabolism, Jagged1 also triggers nuclear, NF-kappa B-dependent transcription of anti-apoptotic gene cIAP-2. This requires recruitment of Notch1, IKK alpha and NE-kappa B to the cIAP-2 promoter. Our observations support a model where Jagged1 triggers IKK alpha-dependent, mitochondrial and nuclear Notch1 signals that stimulate AKT phosphorylation, oxidative metabolism and transcription of survival genes in PTEN wild-type TNBC cells. These data suggest that combination treatments targeting the intersection of the Notch, AKT and NE-kappa B pathways have potential therapeutic applications against CSCs in TNBC cases with Notch1 and wild-type PTEN expression.