Department of Bone and Soft Tissue Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
Key Laboratory of Precision Oncology in Universities of Shandong, Institute of Precision Medicine, Jining Medical University, Jining, 272067, China.
Eur J Pharmacol. 2023 Jul 15;951:175799. doi: 10.1016/j.ejphar.2023.175799. Epub 2023 May 16.
As a key component of the COP9 signalosome complex, which participates in a variety of physiological processes, COPS3 is intimately related to multiple cancers. It promotes cell proliferation, progression and metastasis in several cancer cells. However, whether COPS3 participates in regulating anoikis, a specific kind of apoptosis and functions as an essential modulator of cell metastasis, has not yet been studied. Here, we found COPS3 is highly expressed in several cancers especially in osteosarcoma (OS). Overexpression of COPS3 promoted cell proliferation, cell viability and migration/invasion in both control cells and oxaliplatin (Oxa) treated cells. On the contrary, knockdown of COPS3 further enhanced the cytotoxicity of Oxa. Utilizing bioinformatics analysis, we found that COPS3 was higher expressed in the metastatic group, and associated with the extra-cellular matrix (ECM) receptor interaction pathway, which involve in regulating anoikis. In an anoikis model, COPS3 expression varied and genetic modification of COPS3 influenced the cell death enhanced by Oxa. PFKFB3, an essential modulator of glycolysis, was found to interact with COPS3. Inhibition of PFKFB3 promoted apoptosis and anoikis enhanced by Oxa, and COPS3 overexpression failed to rescue this cell death. On the contrary, in the COPS3 knockdown cells, overexpression of PFKFB3 recovered the anoikis resistance, indicating COPS3 function upstream of PFKFB3. In summary, our results elucidated that COPS3 modulated anoikis via affecting PFKFB3 in OS cancer cells.
作为 COP9 信号体复合物的关键组成部分，参与多种生理过程，COPS3 与多种癌症密切相关。它在几种癌细胞中促进细胞增殖、进展和转移。然而，COPS3 是否参与调节细胞凋亡（一种特殊的细胞程序性死亡形式）以及是否作为细胞转移的重要调节剂尚未得到研究。在这里，我们发现 COPS3 在几种癌症中高度表达，尤其是骨肉瘤（OS）。COPS3 的过表达促进了对照细胞和奥沙利铂（Oxa）处理的细胞中的细胞增殖、细胞活力和迁移/侵袭。相反，COPS3 的敲低进一步增强了 Oxa 的细胞毒性。利用生物信息学分析，我们发现 COPS3 在转移性组中表达更高，并且与细胞外基质（ECM）受体相互作用途径相关，该途径涉及调节细胞凋亡。在细胞凋亡模型中，COPS3 表达发生变化，COPS3 的遗传修饰影响 Oxa 增强的细胞死亡。糖酵解的重要调节剂 PFKFB3 被发现与 COPS3 相互作用。PFKFB3 的抑制促进了由 Oxa 增强的细胞凋亡和细胞凋亡，而过表达的 COPS3 无法挽救这种细胞死亡。相反，在 COPS3 敲低细胞中，过表达 PFKFB3 恢复了对细胞凋亡的抗性，表明 COPS3 功能位于 PFKFB3 上游。总之，我们的结果阐明了 COPS3 通过影响 OS 癌细胞中的 PFKFB3 来调节细胞凋亡。
