未经证实:头颈部鳞状细胞癌(HNSCC)是全球癌症相关死亡的主要原因之一。手术切除,放疗和化疗是HNSCC治疗的主要手段,但往往不能令人满意.顺铂是HNSCC中常用的化疗药物;然而,顺铂耐药是复发和死亡的主要原因。78kD葡萄糖调节蛋白(GRP78)是未折叠蛋白反应(UPR)的主要调节因子,与癌症的治疗抗性有关。GRP78在HNSCC顺铂耐药中的作用尚不清楚。YUM70是一种新发现的羟基喹啉类似物,是GRP78的抑制剂。YUM70在HNSCC细胞系中的作用是未知的。
未经证实:通过siRNA进行GRP78的敲低,以研究GRP78减少在内质网(ER)应激诱导和一般凋亡中的作用。在三种HPV阴性HNSCC细胞系上进行蛋白质印迹检查凋亡标志物。进行WST-1测定以确定细胞活力。相反,我们利用AA147,一种ER蛋白稳定调节因子上调GRP78,并测定细胞凋亡标志物和细胞活力.为了测试YUM70逆转顺铂耐药的能力,顺铂耐药的HNSCC细胞系是通过延长,反复暴露于浓度增加的顺铂。使用顺铂抗性HNSCC细胞系进行集落形成测定以评估体外生殖细胞存活。此外,为了测试YUM70在生理相关系统中逆转顺铂耐药性的能力,我们对顺铂耐药的HNSCC细胞系的3D球体进行了有或没有YUM70的顺铂治疗,并监测了细胞凋亡的发生。
未经证实:降低GRP78水平可诱导HNSCC细胞死亡,而GRP78上调可赋予对顺铂更高的耐药性。顺铂和YUM70联合治疗可增加顺铂耐药HNSCC细胞系中的凋亡标志物,与降低的细胞活力和克隆形成有关。组合治疗还增加了3D球体模型中的凋亡标志物。
UNASSIGNED:GRP78抑制剂YUM70在2D和3D球体模型中降低了HNSCC细胞活力和重新致敏的顺铂抗性HNSCC细胞系,提示YUM70在HNSCC治疗中的潜在用途,包括顺铂耐药的HNSCC。
UNASSIGNED: Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer-related death worldwide. Surgical resection, radiation and chemotherapy are the mainstay of HNSCC treatment but are often unsatisfactory. Cisplatin is a commonly used chemotherapy in HNSCC; however, cisplatin resistance is a major cause of relapse and death. The 78-kD glucose-regulated protein (GRP78) is the master regulator of the unfolded protein response (UPR) and is implicated in therapeutic resistance in cancer. The role of GRP78 in cisplatin resistance in HNSCC remains unclear.
YUM70 is a newly discovered hydroxyquinoline analogue and found to be an inhibitor of GRP78. The effect of
YUM70 in HNSCC cell lines is unknown.
UNASSIGNED: Knockdown of GRP78 by siRNAs was performed to investigate the effect of GRP78 reduction in endoplasmic reticulum (ER)-stress induced and general apoptosis. Western blots examining apoptotic markers were performed on three HPV-negative HNSCC cell lines. WST-1 assay was performed to determine cell viability. In reverse, we utilized AA147, an ER proteostasis regulator to upregulate GRP78, and apoptotic markers and cell viability were determined. To test the ability of
YUM70 to reverse cisplatin resistance, cisplatin-resistant HNSCC cell lines were generated by prolonged, repeated exposure to increasing concentrations of cisplatin. Colony formation assay using the cisplatin-resistant HNSCC cell line was performed to assess the in vitro reproductive cell survival. Furthermore, to test the ability of
YUM70 to reverse cisplatin resistance in a physiologically relevant system, we subjected the 3D spheroids of the cisplatin-resistant HNSCC cell line to cisplatin treatment with or without YUM70 and monitored the onset of apoptosis.
UNASSIGNED: Reduction of GRP78 level induced HNSCC cell death while GRP78 upregulation conferred higher resistance to cisplatin. Combined cisplatin and
YUM70 treatment increased apoptotic markers in the cisplatin-resistant HNSCC cell line, associating with reduced cell viability and clonogenicity. The combination treatment also increased apoptotic markers in the 3D spheroid model.
UNASSIGNED: The GRP78 inhibitor YUM70 reduced HNSCC cell viability and re-sensitized cisplatin-resistant HNSCC cell line in both 2D and 3D spheroid models, suggesting the potential use of YUM70 in the treatment of HNSCC, including cisplatin-resistant HNSCC.