Generation of the Chondroprotective Proteomes by Activating PI3K and TNFα Signaling.
Generation of the Chondroprotective Proteomes by Activating PI3K and TNFα Signaling.
复制标题
DOI：
10.3390/cancers14133039
复制
发表时间：
2022-06-21
期刊：
影响因子：
5.2
通讯作者：
Yokota, Hiroki
中科院分区：
文献类型：
--
作者：
Sun, Xun;Li, Ke-Xin;Figueiredo, Marxa L.;Lin, Chien-Chi;Li, Bai-Yan;Yokota, Hiroki
软骨肉瘤和炎性关节炎是两种损伤关节的疾病。在这里，我们研究了激活致瘤性和炎症信号的反直觉方法是否可以在间充质干细胞和软骨细胞中产生关节保护蛋白质组，用于治疗软骨肉瘤和炎症性关节炎。虽然激活PI3K信号和向软骨肉瘤细胞和软骨细胞注射TNFα促进肿瘤进展和炎症反应，但这些细胞矛盾地产生了软骨保护条件培养基。值得注意的是，软骨保护条件培养基中富集了与GAPDH相互作用的Hsp90ab1。细胞外GAPDH与L1CAM（一种致癌跨膜蛋白）相互作用并抑制致瘤行为，而细胞内GAPDH下调软骨细胞中的p38并发挥抗炎作用。该结果支持生成软骨保护蛋白组的非常规方法。目的：为了开发一种治疗软骨肉瘤（CS）和炎症性关节炎的新方法，我们评估了一种反直觉的方法，即激活致瘤性和炎症信号，以产生关节保护蛋白组。方法：利用间充质干细胞和软骨细胞，通过激活PI3K信号和给药TNFα来产生软骨保护蛋白组。用人类和小鼠细胞系以及小鼠CS模型检测了蛋白质组的功效。利用基于质谱的全基因组蛋白质组学分析其调控机制。结果：虽然通过激活PI3K信号和向CS细胞和软骨细胞注射TNFα可以促进肿瘤进展和炎症反应，但这些细胞矛盾地产生了软骨保护条件培养基（CM）。CM在CS细胞和软骨细胞中下调肿瘤基因TNFα和MMP13的应用。机制上，Hsp90ab1在软骨保护性CM中富集，并免疫沉淀GAPDH。细胞外GAPDH与L1CAM相互作用并抑制致瘤行为，而细胞内GAPDH下调p38并发挥抗炎作用。结论：我们证明了激活致癌和炎症信号的非常规方法可以产生软骨保护蛋白组。Hsp90ab1和GAPDH的作用位置不同，它们是关节组织免受肿瘤和炎症反应的罕见保护者。
Chondrosarcoma and inflammatory arthritis are two joint-damaging diseases. Here, we examined whether a counterintuitive approach of activating tumorigenic and inflammatory signaling may generate joint-protective proteomes in mesenchymal stem cells and chondrocytes for the treatment of chondrosarcoma and inflammatory arthritis. While activating PI3K signaling and the administration of TNFα to chondrosarcoma cells and chondrocytes promoted tumor progression and inflammatory responses, those cells paradoxically generated a chondroprotective conditioned medium. Notably, the chondroprotective conditioned medium was enriched with Hsp90ab1 that interacted with GAPDH. Extracellular GAPDH interacted with L1CAM, an oncogenic transmembrane protein, and inhibited tumorigenic behaviors, whereas intracellular GAPDH downregulated p38 in chondrocytes and exerted anti-inflammatory effects. The result supports the unconventional approach of generating chondroprotective proteomes. Purpose: To develop a novel treatment option for Chondrosarcoma (CS) and inflammatory arthritis, we evaluated a counterintuitive approach of activating tumorigenic and inflammatory signaling for generating joint-protective proteomes. Methods: We employed mesenchymal stem cells and chondrocytes to generate chondroprotective proteomes by activating PI3K signaling and the administration of TNFα. The efficacy of the proteomes was examined using human and mouse cell lines as well as a mouse model of CS. The regulatory mechanism was analyzed using mass spectrometry-based whole-genome proteomics. Results: While tumor progression and inflammatory responses were promoted by activating PI3K signaling and the administration of TNFα to CS cells and chondrocytes, those cells paradoxically generated a chondroprotective conditioned medium (CM). The application of CM downregulated tumorigenic genes in CS cells and TNFα and MMP13 in chondrocytes. Mechanistically, Hsp90ab1 was enriched in the chondroprotective CM, and it immunoprecipitated GAPDH. Extracellular GAPDH interacted with L1CAM and inhibited tumorigenic behaviors, whereas intracellular GAPDH downregulated p38 and exerted anti-inflammatory effects. Conclusions: We demonstrated that the unconventional approach of activating oncogenic and inflammatory signaling can generate chondroprotective proteomes. The role of Hsp90ab1 and GAPDH differed in their locations and they acted as the uncommon protectors of the joint tissue from tumor and inflammatory responses.
登录
查看更多内容
L1CAM 通过刺激 ezrin 转录驱动食管鳞状细胞癌的致癌性
影响因子：
4.7
作者：
Guo, Jin-Cheng;Xie, Yang-Min;Xie, Jian-Jun
通讯作者：
Xie, Jian-Jun
影响因子：
5.8
作者：
Gelderblom, Hans;Hogendoorn, Pancras C. W.;Bovee, Judith V. M. G.
通讯作者：
Bovee, Judith V. M. G.
影响因子：
21.3
作者：
Johnston, LA;Sanders, AL
通讯作者：
Sanders, AL
影响因子：
3.4
作者：
Connelly KE;Hedrick V;Paschoal Sobreira TJ;Dykhuizen EC;Aryal UK
通讯作者：
Aryal UK
影响因子：
5.5
作者：
Li Z;Huang Z;Bai L
通讯作者：
Bai L