Overexpression of ceramide synthase 1 increases C18-ceramide and leads to lethal autophagy in human glioma

// Zheng Wang 1, * , Lijun Wen 1, * , Fei Zhu 1, * , Yanping Wang 1 , Qing Xie 1 , Zijun Chen 2 and Yunsen Li 1 1 Institutes of Biology and Medical Sciences, Medical College, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China 2 Shanghai University of Traditional Chinese Medicine, Shanghai, China * These authors have contributed equally to this work Correspondence to: Zijun Chen, email: zjchen21@aliyun.com.cn Yunsen Li, email: yunsenli@suda.edu.cn Keywords: ceramide synthase 1; C18-ceramide; glioma; mass spectrometry; autophagy Received: March 29, 2017      Accepted: September 25, 2017      Published: October 23, 2017 ABSTRACT Ceramide synthase 1 (CERS1) is the most highly expressed CERS in the central nervous system, and ceramide with an 18-carbon–containing fatty acid chain (C18-ceramide) in the brain plays important roles in signaling and sphingolipid development. However, the roles of CERS1 and C18-ceramide in glioma are largely unknown. In the present study, measured by electrospray ionization linear ion trap mass spectrometry, C18-ceramide was significantly lower in glioma tumor tissues compared with controls ( P < 0.001), indicating that C18-ceramide might have a role in glioma. These roles were examined by reconstitution of C18-ceramide in U251 and A172 glioma cells via addition of exogenous C18-ceramide or overexpression of CERS1, which has been shown to specifically induce the generation of C18-ceramide. Overexpression of CERS1 or adding exogenous C18-ceramide inhibited cell viability and induced cell death by activating endoplasmic reticulum stress, which induced lethal autophagy and inhibited PI3K/AKT signal pathway in U251 and A172 glioma cells. Moreover, overexpression of CERS1 or adding exogenous C18-ceramide increased the sensitivity of U251 and A172 glioma cells to teniposide (VM-26). Thus, the combined therapy of CERS1/C18-ceramide and VM-26 may be a novel therapeutic strategy for the treatment of human glioma.