Genomic analysis of xCT-mediated regulatory network: identification of novel targets against AIDS-associated lymphoma
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Lu Dai1,3, Yueyu Cao1, Yihan Chen1, Johnan A.R. Kaleeba5, Jovanny Zabaleta4 and Zhiqiang Qin1,2
1 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
2 Department of Microbiology/Immunology/Parasitology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA
3 Department of Medicine, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA
4 Department of Pediatrics, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, USA
5 Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
Zhiqiang Qin, email:
Keywords: KSHV, herpesvirus, xCT, lymphoma, microarray
Received: January 29, 2015 Accepted: March 10, 2015 Published: March 30, 2015
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.
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