Nan Peng, Wang Xiao, Li Anan, Ge Yumei, Gu Zongting, Wang Yingying, Tao Ran
Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
Redox Biol. 2025 Jun 8;85:103721. doi: 10.1016/j.redox.2025.103721.
Chemotherapy remains a pivotal strategy in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance has limited the clinical efficacy of chemotherapeutic agents, especially gemcitabine. Here, we identified tetraspanin-15 (TSPAN15), a member of the tetraspanin family, that is frequently overexpressed in human PDAC and is correlated with tumor progression and poor prognosis. Elevated levels of TSPAN15 are involved in mediating gemcitabine resistance of in cancer cells, primarily by inhibiting ferroptosis. Knocking down TSPAN15 increases the sensitivity of PDAC cells to gemcitabine in vitro and in vivo by increasing the susceptibility of cancer cells to ferroptosis. Mechanistically, TSPAN15 directly interacts with integrin-β1 (ITGB1) and maintains its stability by inhibiting ITGB1 ubiquitination. This interaction activates the downstream p-FAK/p-AKT/p-mTOR axis and promotes the expression of glutathione peroxidase 4 (GPX4), a central negative regulator of ferroptosis, ultimately attenuating gemcitabine-induced ferroptosis in PDAC cells. Venetoclax, a newly identified targeted inhibitor of TSPAN15, exhibits synergistic efficacy when combined with gemcitabine for treating PDAC both in vitro and in vivo. This study reveals, for the first time, a major clinically relevant chemoresistance mechanism in PDAC mediated by TSPAN15 in sustaining ITGB1/p-FAK/p-AKT/p-mTOR-GPX4 signaling and tuning ferroptosis, revealing its potential as a viable therapeutic target for chemosensitization.
化疗仍然是胰腺导管腺癌（PDAC）治疗中的关键策略。尽管如此，耐药性的出现限制了化疗药物的临床疗效，尤其是吉西他滨。在此，我们鉴定出四跨膜蛋白-15（TSPAN15），它是四跨膜蛋白家族的一员，在人类PDAC中经常过度表达，并且与肿瘤进展和不良预后相关。TSPAN15水平升高主要通过抑制铁死亡参与介导癌细胞对吉西他滨的耐药性。敲低TSPAN15可通过增加癌细胞对铁死亡的敏感性，在体外和体内提高PDAC细胞对吉西他滨的敏感性。从机制上讲，TSPAN15直接与整合素-β1（ITGB1）相互作用，并通过抑制ITGB1泛素化来维持其稳定性。这种相互作用激活下游的p-FAK/p-AKT/p-mTOR轴，并促进谷胱甘肽过氧化物酶4（GPX4）的表达，GPX4是铁死亡的主要负调节因子，最终减弱吉西他滨诱导的PDAC细胞铁死亡。维奈克拉是一种新鉴定的TSPAN15靶向抑制剂，在体外和体内与吉西他滨联合治疗PDAC时表现出协同疗效。这项研究首次揭示了PDAC中一种主要的临床相关化疗耐药机制，即TSPAN15通过维持ITGB1/p-FAK/p-AKT/p-mTOR-GPX4信号传导和调节铁死亡来介导，揭示了其作为化疗增敏可行治疗靶点的潜力。
