Abstract
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.
Highlights
The oncogenic γ-herpesvirus known as the Kaposi’s sarcoma-associated herpesvirus (KSHV) is a principal causative agent of cancer arising in patients with compromised immune systems [1]
Results xCT is highly expressed on KSHV-infected primary effusion lymphoma (PEL) cell-lines To first identify whether xCT is expressed on KSHVinfected PEL cells, we tested its expression in 3 KSHVinfected PEL cell-lines BC-1, BCP-1 and BCBL-1 (BC-1 was EBV+) using immunoblots
Using a monoclonal Ab recognizing an extracellular domain of xCT in flow cytometry, we confirmed that xCT is highly expressed on the cell surface of KSHV-infected PEL cell-lines including BCP-1 and BCBL-1
Summary
The oncogenic γ-herpesvirus known as the Kaposi’s sarcoma-associated herpesvirus (KSHV) is a principal causative agent of cancer arising in patients with compromised immune systems [1]. One of these cancers, primary effusion lymphoma (PEL), comprises transformed B cells harboring KSHV episome and arises preferentially within the pleural or peritoneal cavities of patients infected with HIV [2]. XCT is highly expressed by a variety of malignant tumors [13,14,15,16], and contributes to multidrug resistance for cancer cells [17,18]
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