Genomic analysis of xCT-mediated regulatory network: Identification of novel targets against AIDS-associated lymphoma.

Lu Dai,Yueyu Cao,Zhiqiang Qin,Yihan Chen,Jovanny Zabaleta,Johnan A.R Kaleeba

doi:10.18632/oncotarget.3710

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), a rapidly progressing malignancy mostly arising in HIV-infected patients. Even under conventional chemotherapy, PEL continues to portend nearly 100% mortality within several months, which urgently requires novel therapeutic strategies. We have previously demonstrated that targeting xCT, an amino acid transporter for cystine/glutamate exchange, induces significant PEL cell apoptosis through regulation of multiple host and viral factors. More importantly, one of xCT selective inhibitors, Sulfasalazine (SASP), effectively prevents PEL tumor progression in an immune-deficient xenograft model. In the current study, we use Illumina microarray to explore the profile of genes altered by SASP treatment within 3 KSHV(+) PEL cell-lines, and discover that many genes involved in oxidative stress/antioxidant defense system, apoptosis/anti-apoptosis/cell death, and cellular response to unfolded proteins/topologically incorrect proteins are potentially regulated by xCT. We further validate 2 downstream candidates, OSGIN1 (oxidative stress-induced growth inhibitor 1) and XRCC5 (X-ray repair cross-complementing protein 5), and evaluate their functional relationship with PEL cell survival/proliferation and chemoresistance, respectively. Together, our data indicate that targeting these novel xCT-regulated downstream genes may represent a promising new therapeutic strategy against PEL and/or other AIDS-related lymphoma.

Highlights

The oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV, known as Human herpesvirus 8) is a principal causative agent of several human cancers including primary effusion lymphoma (PEL), which arises preponderantly in immunocompromised individuals, in particular acquired immune deficiency syndrome (AIDS)patients [1]
We first used the HumanHT-12 v4 Expression BeadChip (Illumina) which contains more than 47,000 probes derived from the NCBI RefSeq Release 38 and other sources to study the gene profile altered between vehicle- or SASP-treated 3 KSHV+ PEL cell-lines (BCP1, BC-1 and BCBL-1)
Our analysis shows that several major cellular functions were affected within SASP-treated PEL cells, including oxidative stress/ antioxidant defense system, apoptosis/anti-apoptosis/ cell death, and cellular response to unfolded proteins/ topologically incorrect proteins, which is consistent with the SASP-induced apoptosis phenotype that we recently observed in KSHV+ PEL cell-lines [5]

Summary

Introduction

The oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV, known as Human herpesvirus 8) is a principal causative agent of several human cancers including primary effusion lymphoma (PEL), which arises preponderantly in immunocompromised individuals, in particular acquired immune deficiency syndrome (AIDS)patients [1]. The oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV, known as Human herpesvirus 8) is a principal causative agent of several human cancers including primary effusion lymphoma (PEL), which arises preponderantly in immunocompromised individuals, in particular acquired immune deficiency syndrome (AIDS). We found that the amino acid transporter, xCT, is highly expressed on the surface of patient-derived KSHV+ PEL cells, and targeting xCT by pharmacological inhibition or RNAi silencing induces significant PEL cell apoptosis [5]. We demonstrated that an xCT selective inhibitor, Sulfasalazine (SASP), effectively prevents PEL tumor progression in an immune-deficient xenograft model [5], which suggests that xCT may represent a promising target for AIDSrelated lymphomas

Methods

Results

Conclusion