The COPS3-FOXO3 positive feedback loop regulates autophagy to promote cisplatin resistance in osteosarcoma.
The COPS3-FOXO3 positive feedback loop regulates autophagy to promote cisplatin resistance in osteosarcoma.
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DOI：
10.1080/15548627.2022.2150003
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发表时间：
2023-06
期刊：
影响因子：
13.3
通讯作者：
Guo, Lei
中科院分区：
文献类型：
--
作者：
Niu, Jianfang;Yan, Taiqiang;Guo, Wei;Wang, Wei;Ren, Tingting;Huang, Yi;Zhao, Zhiqing;Yu, Yiyang;Chen, Chenglong;Huang, Qingshan;Lou, Jingbing;Guo, Lei
化疗是骨肉瘤的重要治疗手段，但化疗耐药性的产生限制了骨肉瘤的治疗效果，并导致预后不良。因此，更好地了解OS化疗耐药的机制是必不可少的。我们以前证明COPS 3/CSN 3（COP 9信号体亚基3）作为癌基因发挥作用，促进OS细胞肺转移，这与化疗耐药性密切相关。在此，我们发现COPS 3在对术前化疗反应差的OS组织中显著上调。此外，COPS 3耗竭使OS细胞在体外和体内对顺铂治疗更敏感，暗示COPS 3是顺铂耐药性的驱动因素。机制研究表明，COPS 3诱导的细胞保护性macroautophagy/自噬响应顺铂。具体来说，我们将FOXO 3确定为COPS 3的关键靶点，因为COPS 3的高表达增强了FOXO 3的核丰度，并增加了FOXO 3响应基因的表达，促进了自噬体的形成和成熟。反过来，FOXO 3通过抑制泛素介导的降解和减弱SKP 2介导的COPS 3抑制来调节COPS 3水平，协同维持高水平的COPS 3。在表达COPS 3的OS细胞和小鼠异种移植模型中，抑制自噬也可以克服对顺铂的耐药性。总的来说，我们的研究结果提供了对顺铂耐药机制的深入了解，并表明靶向COPS 3介导的自噬是克服OS顺铂耐药的一种有前途的治疗策略。缩写：3-MA：3-甲基腺嘌呤; BECN 1：beclin 1; ChIP：染色质免疫沉淀; CHX：放线菌酮; COPS 3/CSN 3：COP 9信号体亚基3; CQ：氯喹; DEG：差异表达基因; FOXO 3：O3叉头箱; GFP：绿色荧光蛋白; IC50：50%抑制浓度; LAMP 1：溶酶体相关膜蛋白1; MAP 1 LC 3B/LC 3B：微管相关蛋白1轻链3 β; MTOR：雷帕霉素激酶的机制靶标; mRFP：单体红色荧光蛋白; OS：骨肉瘤; PBS：磷酸盐缓冲盐水; qRT-PCR：定量实时PCR; RAB 7：RAB 7，RAS癌基因家族成员; RPS 6 KB 1/p70 S6 K1：核糖体蛋白S6激酶B1; SEM：平均值的标准误; shRNA：短发夹RNA; siRNA：小干扰RNA; SKP 2：S期激酶相关蛋白2; TEM：透射电子显微镜; UPS：泛素-蛋白酶体系统
Chemotherapy is an important treatment modality for osteosarcoma (OS), but the development of chemoresistance limits the therapeutic efficacy of OS and results in a poor prognosis. Thus, a better understanding of the mechanisms underlying chemoresistance in OS is essential. We previously demonstrated that COPS3/CSN3 (COP9 signalosome subunit 3) functions as an oncogene to promote OS cells lung metastasis, which is closely related to chemoresistance. Here, we showed that COPS3 was significantly upregulated in OS tissues with poor response to preoperative chemotherapy. Moreover, COPS3 depletion made OS cells more sensitive to cisplatin treatment in vitro and in vivo, implicating COPS3 as a driver of cisplatin resistance. Mechanistic investigations showed that COPS3 induced a cytoprotective macroautophagy/autophagy in response to cisplatin. Specifically, we identified FOXO3 as a critical target of COPS3, as high expression of COPS3 enhanced the nuclear abundance of FOXO3 and increased the expression of FOXO3-responsive genes, promoting autophagosome formation and maturation. In turn, FOXO3 regulated COPS3 levels by inhibiting ubiquitin-mediated degradation and attenuating SKP2-mediated COPS3 inhibition, cooperatively maintaining a high level of COPS3. In both COPS3-expressing OS cells and a murine xenograft model, inhibition of autophagy could also overcome resistance to cisplatin. Collectively, our results offer insights into the mechanisms of cisplatin resistance and suggest that targeting COPS3-mediated autophagy is a promising therapeutic strategy for overcoming the cisplatin resistance of OS. Abbreviations: 3-MA: 3-methyladenine; BECN1: beclin 1; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; COPS3/CSN3: COP9 signalosome subunit 3; CQ: chloroquine; DEGs: differentially expressed genes; FOXO3: forkhead box O3; GFP: green fluorescent protein; IC50: 50% inhibitory concentration; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; mRFP: monomeric red fluorescent protein; OS: osteosarcoma; PBS: phosphate-buffered saline; qRT-PCR: quantitative real-time PCR; RAB7: RAB7, member RAS oncogene family; RPS6KB1/p70S6K1: ribosomal protein S6 kinase B1; SEM: standard error of the mean; shRNA: short hairpin RNA; siRNA: small interfering RNA; SKP2: S-phase kinase associated protein 2; TEM: transmission electron microscopy; UPS: ubiquitin-proteasome system
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