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

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 genomic gene profile 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 functionally validate 2 downstream candidates, OSGIN1 (Oxidative stress-induced growth inhibitor 1) and XRCC5 (X-ray repair cross-complementing protein 5), their relationship with PEL cell survival/proliferation and chemoresistance, respectively. Together, our data indicate that targeting these xCT-regulated novel downstream genes may help devise promising therapeutic strategies against PEL and/or other AIDS-related lymphoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE65418 | GEO | 2015/11/23

SECONDARY ACCESSION(S): PRJNA273954

REPOSITORIES: GEO

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

Project description:Kaposiâs 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 genomic gene profile 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 functionally validate 2 downstream candidates, OSGIN1 (Oxidative stress-induced growth inhibitor 1) and XRCC5 (X-ray repair cross-complementing protein 5), their relationship with PEL cell survival/proliferation and chemoresistance, respectively. Together, our data indicate that targeting these xCT-regulated novel downstream genes may help devise promising therapeutic strategies against PEL and/or other AIDS-related lymphoma. 3 KSHV PEL cell lines were treated with xCT selective inhibitor Sulfasalazine (SASP) and the gene expression signature was compared to that of untreated cells

2015-11-23 | E-GEOD-65418 | biostudies-arrayexpress

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Project description:KSHV is a principal causative agent of primary effusion lymphoma (PEL). Despite this knowledge about the close relationship between HGF/c-MET network and solid tumors development, the role of HGF/c-MET in KSHV-related malignancies remains mostly unclear. We report that HGF/c-MET pathway is highly active within KSHV+ PEL cells and plays important role in tumor cell survival/growth. Targeting HGF/c-MET by a selective inhibitor, PF-2341066, significantly induces PEL apoptosis through a complex of underlying mechanisms, including cell-cycle arrest and DNA damage. By using microarray analysis, we have identified the global gene profile controlled by HGF/c-MET pathway within KSHV+ PEL cell-lines and several novel âdruggableâ candidates closely related to cancer cell survival/growth. Finally, we found that targeting HGF/c-MET pathway by PF-2341066 effectively prevents PEL tumor expansion and/or reduce established lymphoma progression in vivo. PEL cells were treated with vehicle control or c-MET inhibitor PF-2341066 (0.8 ÂµM) for 24 h, and the gene expression signature was compared to respective vehicle controls

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c-MET inhibitor inducing KSHV+ primary effusion lymphoma apoptosis

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2016-01-05 | GSE70594 | GEO

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