Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, No. 14, Section Three, Ren Min Nan Road, Chengdu, Sichuan, 610041, China; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section Three, Ren Min Nan Road, Chengdu, Sichuan, 610041, China.
Biochem Biophys Res Commun. 2020 May 14;525(4):997-1003. doi: 10.1016/j.bbrc.2020.02.164. Epub 2020 Mar 13.
C6-ceramide is an exogenous short-chain ceramide which can induce apoptosis of multiple cancer cells. Salivary adenoid cystic carcinoma (SACC) is a common salivary gland cancer, which possesses of high rate of local recurrence and distant metastasis. The mechanism of ceramide-induced SACC-83 and SACC-LM cell apoptosis has not been revealed. In our study, gene expression microarray was used to discover that the unfolded protein response (UPR) pathway, especially PRKR-like endoplasmic reticulum kinase (PERK) pathway, was the major activated pathway after treatment of c6-ceramide. D1ER, an endoplasmic-reticulum-targeted Ca2+ indicator, was used to measure Ca2+ release from endoplasmic reticulum (ER) dynamically. We found that inositol 1,4,5-trisphosphate receptor 3 (IP3R3) was activated, leading to Ca2+ release from ER, soon after c6-ceramide treatment. IP3R3 silencing could block UPR, although it could not prevent SACC-83 and SACC-LM cells from apoptosis. Moreover, we found that C/EBP-homologous protein could upregulate in a UPR-independent way. Mitochondria outer membrane permeabilization might play an important role in inducing SACC cell apoptosis.
C6-神经酰胺是一种外源性的短链神经酰胺，能够诱导多种癌细胞凋亡。涎腺腺样囊性癌（SACC）是一种常见的涎腺癌，具有较高的局部复发率和远处转移率。神经酰胺诱导 SACC-83 和 SACC-LM 细胞凋亡的机制尚未阐明。在本研究中，我们采用基因表达微阵列技术发现未折叠蛋白反应（UPR）途径，尤其是蛋白激酶 R 样内质网激酶（PERK）途径，是 C6-神经酰胺处理后主要激活的途径。D1ER 是一种内质网靶向的 Ca2+指示剂，用于动态测量内质网（ER）中 Ca2+的释放。我们发现，C6-神经酰胺处理后，很快就会激活肌醇 1,4,5-三磷酸受体 3（IP3R3），导致 ER 中的 Ca2+释放。尽管 IP3R3 沉默不能阻止 SACC-83 和 SACC-LM 细胞凋亡，但它可以阻断 UPR。此外，我们发现 C/EBP 同源蛋白可以以 UPR 非依赖的方式上调。线粒体膜通透性的改变可能在诱导 SACC 细胞凋亡中发挥重要作用。
