title: Genomic analysis of xCT-mediated regulatory network: Identification of novel targets against AIDS-associated lymphoma.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), a rapidly progressing malignancy mostly arising in HIV-infected patients. Even under conventional chemotherapy, PEL continues to portend nearly 100% mortality within several months, which urgently requires novel therapeutic strategies. We have previously demonstrated that targeting xCT, an amino acid transporter for cystine/glutamate exchange, induces significant PEL cell apoptosis through regulation of multiple host and viral factors. More importantly, one of xCT selective inhibitors, Sulfasalazine (SASP), effectively prevents PEL tumor progression in an immune-deficient xenograft model. In the current study, we use Illumina microarray to explore the profile of genes altered by SASP treatment within 3 KSHV(+) PEL cell-lines, and discover that many genes involved in oxidative stress/antioxidant defense system, apoptosis/anti-apoptosis/cell death, and cellular response to unfolded proteins/topologically incorrect proteins are potentially regulated by xCT. We further validate 2 downstream candidates, OSGIN1 (oxidative stress-induced growth inhibitor 1) and XRCC5 (X-ray repair cross-complementing protein 5), and evaluate their functional relationship with PEL cell survival/proliferation and chemoresistance, respectively. Together, our data indicate that targeting these novel xCT-regulated downstream genes may represent a promising new therapeutic strategy against PEL and/or other AIDS-related lymphoma.
authors: Research Center for Translational Medicine and Key Laboratory of Arrhythmias of The Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.|Department of Medicine, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA.
authors: Lu
authors: L
authors: Dai
authors: Research Center for Translational Medicine and Key Laboratory of Arrhythmias of The Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors: Yueyu
authors: Y
authors: Cao
authors: Research Center for Translational Medicine and Key Laboratory of Arrhythmias of The Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors: Yihan
authors: Y
authors: Chen
authors: Department of Microbiology and Immunology, Uniformed Services University of The Health Sciences, Bethesda, MD, USA.
authors: Johnan A R
authors: JA
authors: Kaleeba
authors: Department of Pediatrics, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA.
authors: Jovanny
authors: J
authors: Zabaleta
authors: Research Center for Translational Medicine and Key Laboratory of Arrhythmias of The Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.|Department of Microbiology/Immunology/Parasitology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA.
authors: Zhiqiang
authors: Z
authors: Qin
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics*; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D019288:Herpesvirus 8, Human; D006801:Humans; D015151:Immunoblotting; D054685:Lymphoma, Primary Effusion / Q000235:genetics* / Q000821:virology; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction
chemical_list: D027182:Amino Acid Transport System y+; C118895:SLC7A11 protein, human
keywords: KSHV; herpesvirus; lymphoma; microarray; xCT