Melatonin enhances cisplatin-induced cell death through inhibition of DERL1 in mesenchymal-like CD44high OSCC cells.
Melatonin enhances cisplatin-induced cell death through inhibition of DERL1 in mesenchymal-like CD44high OSCC cells.
复制标题
褪黑激素通过抑制间充质样 CD44 高 OSCC 细胞中的 DERL1 来增强顺铂诱导的细胞死亡。
DOI：
10.1111/jop.13242
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发表时间：
2022
影响因子：
3.3
通讯作者：
Ohta K.
中科院分区：
文献类型：
--
作者：
Shigeishi H;Yokoyama S;Murodumi H;Sakuma M;Fukada S;Okuda S;Yamakado N;Ono S;Takechi M;Ohta K.
褪黑素是一种主要在松果体中产生的激素，参与广泛的生物功能。然而，褪黑激素对化疗诱导的口腔鳞状细胞癌（OSCC）细胞死亡的影响仍有待阐明。本研究的目的是阐明褪黑激素在顺铂诱导的CD44highOSCC细胞毒性中的作用。方法采用纤维连接蛋白包被水凝胶培养scd44highoscc细胞。乳酸脱氢酶细胞毒性试验评估顺铂诱导的细胞死亡。研究褪黑素对顺铂诱导的细胞死亡和Derlin - 1 （DERL1）内质网膜蛋白表达的影响。结果scd44highoscc细胞在纤维连接蛋白包被的水凝胶上培养时表现出间充质样特征。与上皮样CD44highOSCC细胞相比，间充质样CD44highOSCC细胞对顺铂诱导的细胞死亡表现出较强的抵抗力。DERL1mRNA和DERL1蛋白在间充质样CD44highcells中的表达水平明显高于上皮样CD44highcells。derl1sirna敲低后，顺铂诱导的细胞死亡显著增强，表明DERL1参与顺铂诱导的细胞死亡耐药。褪黑素显著抑制DERL1表达，增强顺铂诱导的间充质样cd44high细胞死亡。褪黑激素存在时miR - 181c - 5p表达显著上调。此外，褪黑素抑制的DERL1表达通过mir - 181c - 5抑制剂显著恢复。此外，mir - 181c - 5抑制剂可减弱褪黑素增强的顺铂诱导的细胞死亡。这些结果表明，褪黑素诱导的mir - 181c - 5通过抑制间充质样cd44high细胞中的DERL1而增强顺铂诱导的细胞死亡。结论：在促进顺铂诱导的间充质样CD44highOSCC细胞的细胞毒性中，褪黑素起着至关重要的作用。
BackgroundMelatonin is a hormone that is primarily produced in the pineal gland and is involved in wide range of biological functions. However, the impact of melatonin on chemotherapy‐induced cell death remains to be elucidated in oral squamous cell carcinoma (OSCC) cells. The objective of this study was to clarify the role of melatonin in cisplatin‐induced cytotoxicity in CD44highOSCC cells.MethodsCD44highOSCC cells were cultured on fibronectin‐coated hydrogel. A lactate dehydrogenase cytotoxicity assay was performed to evaluate cisplatin‐induced cell death. The effect of melatonin on cisplatin‐induced cell death and Derlin‐1 (DERL1) endoplasmic reticulum membrane protein expression was investigated.ResultsCD44highOSCC cells exhibited mesenchymal‐like features when cultured on fibronectin‐coated hydrogel. Mesenchymal‐like CD44highOSCC cells demonstrated strong resistance to cisplatin‐induced cell death compared with epithelial‐like CD44highOSCC cells.DERL1mRNA and DERL1 protein expression levels were significantly higher in mesenchymal‐like CD44highcells compared with epithelial‐like CD44highcells. Cisplatin‐induced cell death was significantly enhanced afterDERL1siRNA knockdown, suggesting that DERL1 is involved in resistance to cisplatin‐induced cell death. Melatonin significantly inhibited DERL1 expression and enhanced cisplatin‐induced cell death in mesenchymal‐like CD44highcells.miR‐181c‐5pexpression was significantly upregulated in the presence of melatonin. Furthermore, melatonin‐inhibited DERL1 expression was significantly recovered bymiR‐181c‐5pinhibitor. In addition, melatoninenhanced cisplatin‐induced cell death was attenuated bymiR‐181c‐5pinhibitor. These results suggest that melatonin‐inducedmiR‐181c‐5penhances cisplatin‐induced cell death through inhibition of DERL1 in mesenchymal‐like CD44highcells.ConclusionsMelatonin plays a vital role in promoting cisplatin‐induced cytotoxicity in mesenchymal‐like CD44highOSCC cells.