Targeting xCT, a cystine-glutamate transporter induces apoptosis and tumor regression for KSHV/HIV-associated 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.
Lu
L
Dai
Yueyu
Y
Cao
Yihan
Y
Chen
Chris
C
Parsons
Research Center for Translational Medicine and Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China. zqin@lsuhsc.edu.
Zhiqiang
Z
Qin
D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D003553:Cystine / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D019288:Herpesvirus 8, Human / Q000302:isolation & purification*; D006801:Humans; D016483:Lymphoma, AIDS-Related / Q000378:metabolism* / Q000821:virology; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012514:Sarcoma, Kaposi / Q000378:metabolism* / Q000821:virology; D015398:Signal Transduction; D014162:Transfection; D014764:Viral Proteins / Q000378:metabolism*
D027182:Amino Acid Transport System y+; D005971:Glutamates; C118895:SLC7A11 protein, human; D014764:Viral Proteins; D003553:Cystine