XIAP Limits Autophagic Degradation of Sox2 and Is A Therapeutic Target in Nasopharyngeal Carcinoma Stem Cells.
XIAP Limits Autophagic Degradation of Sox2 and Is A Therapeutic Target in Nasopharyngeal Carcinoma Stem Cells.
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XIAP 限制 Sox2 的自噬降解，是鼻咽癌干细胞的治疗靶点
作者：
Ji J;Yu Y;Li ZL;Chen MY;Deng R;Huang X;Wang GF;Zhang MX;Yang Q;Ravichandran S;Feng GK;Xu XL;Yang CL;Qiu MZ;Jiao L;Yang D;Zhu XF
基本原理：鼻咽癌是华南地区最常见的头颈部肿瘤。NPC中肿瘤干细胞（cancer stem cells，CSCs）的存在有助于肿瘤的维持和治疗抗性，而CSCs逃避凋亡途径的能力可能使其对治疗产生抗性。凋亡抑制蛋白家族蛋白（Inhibitor of apoptosis proteins family proteins，IAPs）在鼻咽癌干细胞中的高表达可能在维持鼻咽癌干细胞特性中发挥重要作用。在这里，我们开发了一种新的CSC靶向策略，通过抑制IAP来治疗NPC。方法：以人鼻咽癌S-18和S-26细胞系为模型，进行体内外实验。采用流式细胞仪（fluorescentactivatedcellsorting，FACS）检测鼻咽SP细胞和CD 44+细胞。通过悬浮培养、集落形成实验和细胞迁移实验鉴定CSCs的特性。采用免疫印迹、免疫沉淀、免疫荧光、磷酸化质谱、siRNA沉默和质粒过表达等方法分析XIAP对Sox 2蛋白稳定性的调节作用以及ERK 1介导的Sox 2信号通路磷酸化。通过免疫组化分析XIAP和Sox 2在鼻咽癌活检组织中的相关性及其在预后中的作用。WST法、免疫印迹法和流式细胞术检测APG-1387或化疗药物诱导S-18和S-26细胞死亡和凋亡。结果如下：IAP，尤其是X染色体连锁IAP（XIAP）在NPC CSC中表达增加，这些蛋白通过增强Sox 2的稳定性，参与CSC特性的维持。在非CSC中，ERK 1激酶通过Sox 2在Ser 251处的磷酸化和Sox 2在Lys 245处的进一步SUMO化促进Sox 2的自噬降解。然而，XIAP通过抑制CSC中ERK 1的活化来阻断Sox 2的自噬降解。此外，XIAP与Sox 2在鼻咽癌组织中的表达呈正相关，而Sox 2与鼻咽癌的进展有关。最后，我们发现一种新的IAP拮抗剂APG-1387对CSCs具有抗肿瘤作用。APG-1387与CDDP /5-FU联合应用对NPC有协同作用。结论：我们的研究强调了IAP在NPC CSC维持中的重要性。因此，XIAP是CSCs中有希望的治疗靶点，提示APG-1387与常规化疗联合治疗NPC患者可能获益。
Rationale: Nasopharyngeal carcinoma (NPC) is the most frequent head and neck tumor in South China. The presence of cancer stem cells (CSCs) in NPC contributes to tumor maintenance and therapeutic resistance, while the ability of CSCs to escape from the apoptosis pathway may render them the resistant property to the therapies. Inhibitor of apoptosis proteins family proteins (IAPs), which are overexpressed in nasopharyngeal carcinoma stem cells, may play an important role in maintaining nasopharyngeal cancer stem cell properties. Here, we develop a novel CSC-targeting strategy to treat NPC through inhibiting IAPs. Methods: Human NPC S-18 and S-26 cell lines were used as the model system in vitro and in vivo. Fluorescence activated cell sorting (FACS) assay was used to detect nasopharyngeal SP cells and CD44+ cells. The characteristics of CSCs were defined by sphere suspension culture, colony formation assay and cell migration. The role of XIAP on the regulation of Sox2 protein stability and ERK1-mediated phosphorylation of Sox2 signaling pathway were analyzed using immunoblotting, immunoprecipitation, immunofluorescence, phosphorylation mass spectrometry, siRNA silencing and plasmid overexpression. The correlation between XIAP and Sox2 in NPC biopsies and their role in prognosis was performed by immunohistochemistry. APG-1387 or chemotherapies-induced cell death and apoptosis in S-18 and S-26 were determined by WST, immunoblotting and flow cytometry assay. Results: IAPs, especially X chromosome-linked IAP (XIAP), were elevated in CSCs of NPC, and these proteins were critically involved in the maintenance of CSCs properties by enhancing the stability of Sox2. Mechanistically, ERK1 kinase promoted autophagic degradation of Sox2 via phosphorylation of Sox2 at Ser251 and further SUMOylation of Sox2 at Lys245 in non-CSCs. However, XIAP blocked autophagic degradation of Sox2 by inhibiting ERK1 activation in CSCs. Additionally, XIAP was positively correlated with Sox2 expression in NPC tissues, which were associated with NPC progression. Finally, we discovered that a novel antagonist of IAPs, APG-1387, exerted antitumor effect on CSCs. Also, the combination of APG-1387 with CDDP /5-FU has a synergistic effect on NPC. Conclusion: Our study highlights the importance of IAPs in the maintenance of CSCs in NPC. Thus, XIAP is a promising therapeutic target in CSCs and suggests that NPC patients may benefit from a combination treatment of APG-1387 with conventional chemotherapy.
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