Tunicamycin-induced endoplasmic reticulum stress inhibits chemoresistance of FaDu hypopharyngeal carcinoma cells in 3D collagen I cultures and in vivo
Tunicamycin-induced endoplasmic reticulum stress inhibits chemoresistance of FaDu hypopharyngeal carcinoma cells in 3D collagen I cultures and in vivo
复制标题
衣霉素诱导的内质网应激可抑制 3D I 型胶原培养物和体内 FaDu 下咽癌细胞的化疗耐药性。
DOI：
10.1016/j.yexcr.2021.112725
复制
发表时间：
2021-07-06
影响因子：
3.7
通讯作者：
Mi, Kun
中科院分区：
文献类型：
--
作者：
Gu, Cuirong;Zhang, Yue;Mi, Kun
晚期头颈部鳞状细胞癌（HNSCC）患者的预后受到化疗耐药性的广泛影响。胶原I作为一种培养支架，可促进癌细胞的CSC （cancer stem cell）特性，可作为研究HNSCC化疗耐药的体外模型。内质网（Endoplasmic reticulum， ER）应激是一种影响肿瘤进展和促进某些药物抗肿瘤作用的细胞应激状态。然而，内质网应激对I型胶原诱导的CSC性质和HNSCC细胞化疗耐药的影响尚未得到解决。在本研究中，我们在3D（三维）I型胶原培养和小鼠异种移植模型中研究了tunicamycin （TM）诱导的内质网应激对FaDu下咽癌细胞干性和对化疗药物敏感性的影响。我们的研究表明，胶原I支架促进了CSC的特性，增加了3D培养中FaDu细胞的G1群，同时伴随着整合素β 1的成熟和活化的tgf - β 1浓度的增强。与2D（二维）培养的细胞相比，3D I型胶原支架中的细胞对顺铂和紫杉醇等化疗药物的耐药性明显增加。进一步分析发现，TM诱导内质网应激优先减弱FaDu细胞在3D I型胶原中的化学耐药，下调其CSC特性和tgf - β 1浓度，导致整合素β 1去糖基化。在小鼠异种移植模型中进一步评估了TM，与紫杉醇联合使用比TM或紫杉醇单独使用更能抑制肿瘤生长。综上所述，我们的研究结果表明，tm诱导的内质网应激增强了FaDu细胞在3D培养和体内的抗癌功效，并强调了内质网应激条件下靶向化疗耐药癌症干细胞的意义。
The prognosis in patients with advanced head and neck squamous cell carcinoma (HNSCC) is widely affected by the resistance to chemotherapy. As a culture scaffold, collagen I was showed to promote CSC (cancer stem cell) properties of cancer cells which could be used as in vitro models to study the chemoresistance in HNSCC. Endoplasmic reticulum (ER) stress is a cellular stress condition which could affect tumor progression and promote the anti-tumor effects of certain drugs. However, the impact of ER stress on collagen I induced CSC properties and chemoresistance of HNSCC cells has not been addressed. In this study we investigated the effects of tunicamycin (TM) induced ER stress on the stemness and sensitivity to chemotherapeutic drugs of FaDu hypopharyngeal carcinoma cells in 3D (three-dimensional) collagen I cultures and mouse xenograft models. Our study revealed that Collagen I scaffold promoted CSC properties and increased G1 population of FaDu cells in 3D cultures, accompanied by maturation of integrin beta 1 and enhanced activated TGF-beta 1 concentration. Compared to 2D (two-dimensional) cultured cells, cells in 3D Collagen I scaffold exhibited significantly increased resistance to chemotherapeutic drugs of cisplatin and paclitaxel. Further analysis revealed that TM induced ER stress preferentially attenuated chemoresistance of FaDu cells in 3D collagen I, downregulated their CSC properties and TGF-beta 1 concentration and resulted in deglycosylation of integrin beta 1. TM was further evaluated in the mouse xenograft models and showed significant tumor growth inhibition in combination with paclitaxel than either TM or paclitaxel alone. Taken together, Our findings suggest that TM-induced ER stress potentiates anticancer efficacy of FaDu cells in 3D cultures and in vivo, and highlight implications for targeting chemotherapy-resistant cancer stem cells under ER stress conditions.