Li Xuan, Zhao Yan, Liu Yang, Zhang Chang-Song, Xu Zhao-Yuan, Wang Shi-Rui, Zhang Tong-Mei, Zhang Yan, Liang Su-Xia, Yan Ying-Bin
Tianjin Medical University, 22 Qi-xiang-tai Road, Heping District, Tianjin 300070, China; Department of Oromaxillofacial-Head and Neck Surgery, Tianjin Stomatological Hospital, School of Medicine, Nankai University, 75 Dagu Road, Heping District, Tianjin 300041, China; Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, 75 Dagu Road, Heping District, Tianjin 300041, China.
Department of Oromaxillofacial-Head and Neck Surgery, Tianjin Stomatological Hospital, School of Medicine, Nankai University, 75 Dagu Road, Heping District, Tianjin 300041, China; Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, 75 Dagu Road, Heping District, Tianjin 300041, China.
Cell Signal. 2025 Oct;134:111908. doi: 10.1016/j.cellsig.2025.111908. Epub 2025 May 27.
Pannexin 3 (Panx3) has been the subject of numerous studies across different cell types, predominantly concentrating on bone remodeling, wound repair, and dermal inflammation. However, the link between Panx3 and cancer remains minimally explored. Here, we showed for the first time that the expression of Panx3 was lower in oral squamous cell carcinoma (OSCC) tissues than in normal oral mucosa tissues, and was associated with the differentiation of OSCC. We found that overexpression of Panx3 significantly promotes ferroptosis while inhibiting proliferation, migration, and invasion in SCC15 and CAL27 cells. Furthermore, in Panx3-overexpressing OSCC cells, the expression levels of P-AKT, P-mTOR, GPX4, and SLC7A11 were significantly decreased, whereas ACSL4 expression was markedly upregulated. Subsequently, the enhanced ferroptosis was significantly rescued upon the addition of the AKT activator SC79 to Panx3-overexpressing SCC15 and CAL27 cells. The tumor-suppressive role of Panx3 through ferroptosis induction was further confirmed by xenograft assays, which demonstrated significantly inhibited tumor growth. In conclusion, the results suggested that Panx3 overexpression reduced the survival of OSCC cells and inhibited the progression of OSCC by promoting ferroptosis via the inhibition of AKT/mTOR signaling pathway.
泛连接蛋白3（Panx3）一直是不同细胞类型众多研究的主题，主要集中在骨重塑、伤口修复和皮肤炎症方面。然而，Panx3与癌症之间的联系仍鲜有探索。在此，我们首次表明，Panx3在口腔鳞状细胞癌（OSCC）组织中的表达低于正常口腔黏膜组织，且与OSCC的分化相关。我们发现，Panx3的过表达显著促进铁死亡，同时抑制SCC15和CAL27细胞的增殖、迁移和侵袭。此外，在过表达Panx3的OSCC细胞中，P-AKT、P-mTOR、GPX4和SLC7A11的表达水平显著降低，而ACSL4的表达明显上调。随后，在过表达Panx3的SCC15和CAL27细胞中加入AKT激活剂SC79后，增强的铁死亡得到显著挽救。异种移植试验进一步证实了Panx3通过诱导铁死亡发挥的肿瘤抑制作用，该试验表明肿瘤生长受到显著抑制。总之，结果表明，Panx3过表达通过抑制AKT/mTOR信号通路促进铁死亡，从而降低OSCC细胞的存活率并抑制OSCC的进展。
