Yang Bo, Lou Chao, Chen Shengkai, Zhang Zhiyuan, Xu Qin
Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Mol Cancer Res. 2023 Feb 1;21(2):127-139. doi: 10.1158/1541-7786.MCR-22-0415.
Anoikis resistance is a prerequisite for circulating tumor cells to survive. However, the mechanism underlying anoikis resistance is poorly understood. In the current study, the effect of TNF receptor-associated factor 6 (TRAF6)-induced NF-kB activation on anoikis susceptibility in tumor cells was evaluated. Differential TRAF6-binding proteins in anoikis-sensitive versus anoikis-resistant tumor cells were screened by LC/MS-MS analysis. The effects of TRAF6-binding proteins on the stability of TRAF6, the activation of NF-kB signaling and anoikis susceptibility in tumor cells were detected. We found that the loss of TRAF6 expression is an important molecular event linked to anoikis. X-linked inhibitor of apoptosis protein (XIAP), an E3 ligase, can bind, ubiquitinate, and degrade TRAF6 and may lead to inactivation of NF-κB signaling and anoikis sensitivity. High expression of prohibitin 1 (PHB1) competes with XIAP for binding to TRAF6 and confers anoikis resistance to tumor cells. PHB1 and TRAF6 knockdown eliminated tumor cells from the circulation in vivo. Significant correlations between elevated PHB1 and TRAF6 expression and distant metastasis were observed in patients with oral cancer. Collectively, we elucidated a novel mechanism governing anoikis. Our data also indicated that TRAF6 and PHB1 are potential therapeutic targets for tumor cells disseminating in the circulation.
Our data implicate that PHB1 competes with XIAP for binding to TRAF6 and confers anoikis resistance to tumor cells.
失巢凋亡抗性是循环肿瘤细胞存活的先决条件。然而，失巢凋亡抗性的潜在机制仍知之甚少。在本研究中，评估了肿瘤坏死因子受体相关因子6（TRAF6）诱导的核因子κB（NF-κB）激活对肿瘤细胞失巢凋亡敏感性的影响。通过液相色谱-串联质谱分析筛选失巢凋亡敏感与失巢凋亡抗性肿瘤细胞中差异表达的TRAF6结合蛋白。检测TRAF6结合蛋白对TRAF6稳定性、NF-κB信号激活及肿瘤细胞失巢凋亡敏感性的影响。我们发现TRAF6表达缺失是与失巢凋亡相关的重要分子事件。X连锁凋亡抑制蛋白（XIAP）作为一种E3连接酶，可结合、泛素化并降解TRAF6，可能导致NF-κB信号失活和失巢凋亡敏感性。抗增殖蛋白1（PHB1）的高表达与XIAP竞争结合TRAF6，赋予肿瘤细胞失巢凋亡抗性。敲低PHB1和TRAF6可使体内循环中的肿瘤细胞清除。在口腔癌患者中观察到PHB1和TRAF6表达升高与远处转移之间存在显著相关性。总体而言，我们阐明了一种调控失巢凋亡的新机制。我们的数据还表明，TRAF6和PHB1是循环中播散肿瘤细胞的潜在治疗靶点。
我们的数据表明，PHB1与XIAP竞争结合TRAF6，赋予肿瘤细胞失巢凋亡抗性。
