化疗耐药是晚期舌鳞癌预后差的重要原因，既往发现巴弗洛霉素（Baf）A1通过阻断自噬增强化疗敏感性，然而我们发现Baf A1通过非自噬阻断机制增强舌鳞癌对顺铂的敏感性。最近发现溶酶体与耐药有关，然而其是否与Baf A1增强顺铂化疗敏感性有关尚不清楚。我们发现，顺铂可经c-Abl/GSK3通路介导TFEB去磷酸化入核促进溶酶体合成，继而经溶酶体“扣押”及“胞吐”铂离子导致舌鳞癌顺铂耐药；而Baf A1通过抑制溶酶体功能逆转耐药是其增强顺铂化疗敏感性的核心机制。本课题拟用对顺铂敏感和耐药的舌鳞癌细胞为研究对象，采用Baf A1、c-Abl抑制剂Nilotinib、siTFEB、胞吐作用抑制剂U18666A等进行干预，探索干预措施对舌鳞癌细胞凋亡的影响及其机制；继之验证“顺铂+溶酶体功能干扰”模式对舌鳞癌移植瘤的抑制作用，证实溶酶体可作为提高顺铂化疗敏感性的潜在靶点，为头颈鳞癌综合治疗提供新思路。

Drug resistance is an important cause of poor prognosis for the patients with advanced tongue squamous cell carcinoma. It was shown that Bafilomycin (Baf) A1 can enhance some drugs toxicity by blocking autophagy. However, we found that Baf A1 can enhance the sensitivity of tongue squamous carcinoma cells to cisplatin through non-autophagy blocking mechanism. Lysosomes have recently been found to be associated with multidrug resistance. However, it is not clear whether it is related to the increased chemosensitivity of tongue squamous carcinoma cells to cisplatin. We found that cisplatin can promote lysosomal synthesis by c-Abl/GSK3 pathway inducing TFEB into nucleus after dephosphorylation, and then lead to cisplatin resistance via lysosome “sequestration” and “exocytosis” of platinum ion in tongue squamous carcinoma cells. Baf A1 reversion of cisplatin toxicity by inhibiting lysosomal acidification is its core mechanism for enhancing chemosensitivity of tongue squamous carcinoma cells to cisplatin. In this project, we will use tongue squamous carcinoma cells sensitive and resistant to cisplatin as tools. Baf A1, inhibitor of c-Abl (Nilotinib), siTFEB and inhibitor of exocytosis (U18666A) will be used as lysosome interference methods. The effect of intervention on apoptosis of tongue squamous carcinoma cells and its mechanism will be detected and analyzed. Further study on the inhibitory effect of "cisplatin + lysosome interference" model on the xenograft tumor in nude mouse will be explored. We hope it will be confirmed that lysosome can be used as a potential target for enhancing the chemosensitivity of cisplatin in the tongue squamous carcinoma cells. New ideas for comprehensive treatment of head and neck squamous cell carcinoma will be supplied in the future.