Gu Cuirong, Zhang Yue, Chen Dan, Liu Huifen, Mi Kun
Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Clinical Laboratory, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Exp Cell Res. 2021 Aug 15;405(2):112725. doi: 10.1016/j.yexcr.2021.112725. Epub 2021 Jul 3.
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 β1 and enhanced activated TGF-β1 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-β1 concentration and resulted in deglycosylation of integrin β1. 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.
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。作为一种培养支架，I型胶原被证明可促进癌细胞的癌症干细胞（CSC）特性，这可作为体外模型用于研究HNSCC中的化疗耐药性。内质网（ER）应激是一种细胞应激状态，可影响肿瘤进展并增强某些药物的抗肿瘤作用。然而，ER应激对I型胶原诱导的HNSCC细胞CSC特性和化疗耐药性的影响尚未得到研究。在本研究中，我们调查了衣霉素（TM）诱导的ER应激对三维（3D）I型胶原培养物和小鼠异种移植模型中FaDu下咽癌细胞干性及对化疗药物敏感性的影响。我们的研究表明，I型胶原支架在3D培养中促进了FaDu细胞的CSC特性并增加了G1期细胞比例，同时伴随着整合素β1的成熟和活化TGF-β1浓度的升高。与二维（2D）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显著增加。进一步分析表明，TM诱导的ER应激优先减弱了3D I型胶原中FaDu细胞的化疗耐药性，下调了它们的CSC特性和TGF-β1浓度，并导致整合素β1去糖基化。TM在小鼠异种移植模型中进一步评估，结果显示与单独使用TM或紫杉醇相比，与紫杉醇联合使用时具有显著的肿瘤生长抑制作用。综上所述，我们的研究结果表明，TM诱导的ER应激增强了3D培养物和体内FaDu细胞的抗癌疗效，并突出了在ER应激条件下靶向化疗耐药癌症干细胞的意义。
