Targeting xCT, a cystine-glutamate transporter induces apoptosis and tumor regression for KSHV/HIV-associated lymphoma

被引:50
作者
Dai, Lu [1 ,2 ,4 ]
Cao, Yueyu [1 ,2 ]
Chen, Yihan [1 ,2 ]
Parsons, Chris [4 ]
Qin, Zhiqiang [1 ,2 ,3 ]
机构
[1] Tongji Univ, East Hosp, Sch Med, Res Ctr Translat Med, Shanghai 200120, Peoples R China
[2] Tongji Univ, East Hosp, Sch Med, Key Lab Arrhythmias,Minist Educ China, Shanghai 200120, Peoples R China
[3] Louisiana State Univ, Hlth Sci Ctr, Louisiana Canc Res Ctr, Dept Microbiol Immunol Parasitol, New Orleans, LA 70112 USA
[4] Louisiana State Univ, Hlth Sci Ctr, Louisiana Canc Res Ctr, Dept Med, New Orleans, LA 70112 USA
基金
中国国家自然科学基金; 美国国家卫生研究院;
关键词
KSHV; Herpesvirus; xCT; Lymphoma; PRIMARY EFFUSION LYMPHOMA; DUAL INHIBITION; DNA-SEQUENCES; POTENTIAL USE; CANCER; SULFASALAZINE; EXPRESSION; GROWTH; SUPPRESSION; RESISTANCE;
D O I
10.1186/1756-8722-7-30
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), which represents a rapidly progressing malignancy arising in HIV-infected patients. Conventional chemotherapy for PEL treatment induces unwanted toxicity and is ineffective - PEL continues to portend nearly 100% mortality within a period of months, which requires novel therapeutic strategies. The amino acid transporter, xCT, is essential for the uptake of cystine required for intracellular glutathione (GSH) synthesis and for maintaining the intracellular redox balance. Inhibition of xCT induces growth arrest in a variety of cancer cells, although its role in virus-associated malignancies including PEL remains unclear. In the current study, we identify that xCT is expressed on the surface of patient-derived KSHV+ PEL cells, and targeting xCT induces caspase-dependent cell apoptosis. Further experiments demonstrate the underlying mechanisms including host and viral factors: reducing intracellular GSH while increasing reactive oxygen species (ROS), repressing cell-proliferation-related signaling, and inducing viral lytic genes. Using an immune-deficient xenograft model, we demonstrate that an xCT selective inhibitor, Sulfasalazine (SASP), prevents PEL tumor progression in vivo. Together, our data provide innovative and mechanistic insights into the role of xCT in PEL pathogenesis, and the framework for xCT-focused therapies for AIDS-related lymphoma in future.
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页数:12
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