Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China.
J Cell Physiol. 2018 Dec;233(12):9416-9425. doi: 10.1002/jcp.26815. Epub 2018 Jul 27.
Chemoresistance remains a challenge in the effective treatment of solid tumors, including oral squamous cell carcinoma (OSCC). Mitochondrial dynamics and autophagy have recently been implicated in the chemoresistance of cancer cells. The neutralization of ceramide is also associated with multidrug resistance, and ceramide synthase 6 (CerS6) is known to induce apoptosis. However, whether CerS6 regulates chemoresistance in OSCC is not clearly understood. Therefore, we investigated the role of CerS6 in the susceptibility of OSCC cells to cisplatin. In this study, we observed that cisplatin-resistant OSCC cells process lower levels of fission-state mitochondria and cell apoptosis than cisplatin-sensitive cells, and autophagy was activated in cisplatin-resistant OSCC cells. We found lower CerS6 expression in cisplatin-resistant OSCC cells. Overexpression of CerS6 with lentivirus-encoded CerS6 complementary DNA in cisplatin-resistant OSCC cells increased cisplatin sensitivity. Overexpression of CerS6 enhanced mitochondrial fission and apoptosis and attenuated cisplatin-induced autophagy in cisplatin-resistant OSCC cells. Further investigation indicated that CerS6 might function through altering calpain expression to enhance cisplatin sensitivity. Cisplatin-resistant OSCC cells xenografted onto a nude mouse model confirmed that CerS6 enhanced cisplatin chemotherapy sensitivity to reduce tumor volume. These data indicate that CerS6 could mediate an effective response to cisplatin in chemoresistant OSCC.
化疗耐药性仍然是实体瘤有效治疗的一个挑战，包括口腔鳞状细胞癌（OSCC）。线粒体动力学和自噬最近被认为与癌细胞的化疗耐药性有关。神经酰胺的中和也与多药耐药性有关，并且已经知道神经酰胺合酶 6（CerS6）诱导细胞凋亡。然而，CerS6 是否调节 OSCC 中的化疗耐药性尚不清楚。因此，我们研究了 CerS6 在 OSCC 细胞对顺铂敏感性中的作用。在这项研究中，我们观察到顺铂耐药性 OSCC 细胞中的分裂状态线粒体和细胞凋亡水平低于顺铂敏感性细胞，并且自噬在顺铂耐药性 OSCC 细胞中被激活。我们发现顺铂耐药性 OSCC 细胞中的 CerS6 表达水平较低。用慢病毒编码 CerS6 cDNA 过表达 CerS6 可增加顺铂耐药性 OSCC 细胞的顺铂敏感性。CerS6 的过表达增强了线粒体分裂和凋亡，并减轻了顺铂诱导的顺铂耐药性 OSCC 细胞中的自噬。进一步的研究表明，CerS6 可能通过改变钙蛋白酶的表达来增强顺铂敏感性。CerS6 增强顺铂化疗敏感性以减少肿瘤体积的顺铂耐药性 OSCC 细胞异种移植到裸鼠模型中得到证实。这些数据表明 CerS6 可以介导对化疗耐药性 OSCC 中顺铂的有效反应。
