Transcriptomic and functional pathways analysis of ascorbate-induced cytotoxicity and resistance of Burkitt lymphoma

// Zenglin Pei 1, * , Xuan Zhang 1, * , Chunxia Ji 1 , Song-Mei Liu 2 , Jin Wang 1 1 Scientific Research Center, Shanghai Public Health Clinical Center, Jinshan District, Shanghai 201508, China 2 Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China * These authors contributed equally to this work Correspondence to: Jin Wang, email: wangjin@shaphc.org Keywords: drug resistance, transcriptomic profiles, pathway analysis, ascorbate, Burkitt lymphoma cells Received: April 14, 2016      Accepted: August 24, 2016      Published: August 31, 2016 ABSTRACT Ascorbate is a pro-oxidant that generates hydrogen peroxide–dependent cytotoxity in cancer cells without adversely affecting normal cells. To determine the mechanistic basis for this phenotype, we selected Burkitt lymphoma cells resistant to ascorbate (JLPR cells) and their ascorbate-sensitive parental cells (JLPS cells). Compared with JLPS cells, the increased glucose uptake in JLPR cells (with upregulated glucose transporters, increased antioxidant enzyme activity, and altered cell cycling) conferred ascorbate–induced cytotoxicity and resistance. Transcriptomic profiles and function pathway analysis identified differentially expressed gene signatures for JLPR cells and JLPS cells, which differential expression levels of five genes ( ATF5, CD79B, MHC, Myosin , and SAP18 ) in ascorbate-resistant cells were related to phosphoinositide 3 kinase, cdc42 , DNA methylation and transcriptional repression, polyamine regulation, and integrin-linked kinase signaling pathways. These results suggested that coordinated changes occurred in JLPR cells to enable their survival when exposed to the cytotoxic pro-oxidant stress elicited by pharmacologic ascorbate treatment.