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
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated