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

[primary effusion lymphoma]

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 .

Diseases
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Diseases presenting "deficient xenograft model" symptom

primary effusion lymphoma

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