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

Dai L, Cao Y, Chen Y, Kaleeba JA, Zabaleta J, Qin Z - Oncotarget (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Translational Medicine and Key Laboratory of Arrhythmias of The Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.

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.

No MeSH data available.


Related in: MedlinePlus

The top 2 scored maps (maps with the lowest p-value) based on the enrichment distribution sorted by ‘common’ gene set(A) Oxidative stress: Role of Sirtuin1 and PGC1 alpha in activation of antioxidant defense system. (B) Apoptosis and survival: Role of IAP proteins in apoptosis. Experimental data from all files is linked to and visualized on the maps as thermometer like figures. Up-ward thermometers have red color and indicate upregulated signals and down ward (blue) ones indicate downregulated expression levels of the genes. Data was produced by the Metacore Software (Thompson Reuters).
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Figure 3: The top 2 scored maps (maps with the lowest p-value) based on the enrichment distribution sorted by ‘common’ gene set(A) Oxidative stress: Role of Sirtuin1 and PGC1 alpha in activation of antioxidant defense system. (B) Apoptosis and survival: Role of IAP proteins in apoptosis. Experimental data from all files is linked to and visualized on the maps as thermometer like figures. Up-ward thermometers have red color and indicate upregulated signals and down ward (blue) ones indicate downregulated expression levels of the genes. Data was produced by the Metacore Software (Thompson Reuters).

Mentions: 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 (BCP-1, BC-1 and BCBL-1). Intersection analysis indicated that there were totally 100 common genes significantly altered within all the 3 SASP-treated cell-lines (up/down≥2 folds and p < 0.05); 33 similar genes altered between BCBL-1 and BC-1, 93 similar between BCBL-1 and BCP-1, and 124 similar between BC-1 and BCP-1; 80 genes altered were unique to BCBL-1, 150 unique to BCP-1 and 640 unique to BC-1 (Figure 1). Notably, BC-1 cells, which are also EBV+, had a much higher number of uniquely altered genes than BCBL-1 and BCP-1. Within the common gene set, the top 20 upregulated or downregulated candidate genes in SASP-treated BCP-1, BC-1 and BCBL-1 cell-lines are listed in Table 1 and Table 2, respectively, including gene description and the altered level of transcription in these cell-lines. Interestingly, we found that the functional role of most genes in PEL pathogenesis have never been reported, although some of them have been implicated in other types of malignancies. For example, SRXN1 (Sulfiredoxin-1), which is upregulated in all three SASP-treated PEL cell lines (Table 1) is involved in proliferation inhibition of acute myeloid leukemia mediated by Maesopsin 4-O-beta-D-glucoside, a natural compound isolated from the leaves of Artocarpus tonkinensis) [21]. Another study reported that activation of PFKP (6-phosphofructokinase type C), which is downregulated in SASP-treated PEL cells (Table 2) is closely associated with breast cancer cell proliferation [22]. The opposite effects of SASP on SRXN1 and PFKP transcription underscores the putative benefits of this drug in clinical management of PEL as well. We next performed enrichment analysis of these common, similar and unique sets of genes using the Pathway map, Gene Ontology (GO) Processes and Process Networks modules from Metacore Software (Thompson Reuters) [23]. 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]. The top 2 scored pathway maps and protein networks based on the enrichment analysis of “common” gene set were listed in Figures 3 and S1, respectively.


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

Dai L, Cao Y, Chen Y, Kaleeba JA, Zabaleta J, Qin Z - Oncotarget (2015)

The top 2 scored maps (maps with the lowest p-value) based on the enrichment distribution sorted by ‘common’ gene set(A) Oxidative stress: Role of Sirtuin1 and PGC1 alpha in activation of antioxidant defense system. (B) Apoptosis and survival: Role of IAP proteins in apoptosis. Experimental data from all files is linked to and visualized on the maps as thermometer like figures. Up-ward thermometers have red color and indicate upregulated signals and down ward (blue) ones indicate downregulated expression levels of the genes. Data was produced by the Metacore Software (Thompson Reuters).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494968&req=5

Figure 3: The top 2 scored maps (maps with the lowest p-value) based on the enrichment distribution sorted by ‘common’ gene set(A) Oxidative stress: Role of Sirtuin1 and PGC1 alpha in activation of antioxidant defense system. (B) Apoptosis and survival: Role of IAP proteins in apoptosis. Experimental data from all files is linked to and visualized on the maps as thermometer like figures. Up-ward thermometers have red color and indicate upregulated signals and down ward (blue) ones indicate downregulated expression levels of the genes. Data was produced by the Metacore Software (Thompson Reuters).
Mentions: 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 (BCP-1, BC-1 and BCBL-1). Intersection analysis indicated that there were totally 100 common genes significantly altered within all the 3 SASP-treated cell-lines (up/down≥2 folds and p < 0.05); 33 similar genes altered between BCBL-1 and BC-1, 93 similar between BCBL-1 and BCP-1, and 124 similar between BC-1 and BCP-1; 80 genes altered were unique to BCBL-1, 150 unique to BCP-1 and 640 unique to BC-1 (Figure 1). Notably, BC-1 cells, which are also EBV+, had a much higher number of uniquely altered genes than BCBL-1 and BCP-1. Within the common gene set, the top 20 upregulated or downregulated candidate genes in SASP-treated BCP-1, BC-1 and BCBL-1 cell-lines are listed in Table 1 and Table 2, respectively, including gene description and the altered level of transcription in these cell-lines. Interestingly, we found that the functional role of most genes in PEL pathogenesis have never been reported, although some of them have been implicated in other types of malignancies. For example, SRXN1 (Sulfiredoxin-1), which is upregulated in all three SASP-treated PEL cell lines (Table 1) is involved in proliferation inhibition of acute myeloid leukemia mediated by Maesopsin 4-O-beta-D-glucoside, a natural compound isolated from the leaves of Artocarpus tonkinensis) [21]. Another study reported that activation of PFKP (6-phosphofructokinase type C), which is downregulated in SASP-treated PEL cells (Table 2) is closely associated with breast cancer cell proliferation [22]. The opposite effects of SASP on SRXN1 and PFKP transcription underscores the putative benefits of this drug in clinical management of PEL as well. We next performed enrichment analysis of these common, similar and unique sets of genes using the Pathway map, Gene Ontology (GO) Processes and Process Networks modules from Metacore Software (Thompson Reuters) [23]. 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]. The top 2 scored pathway maps and protein networks based on the enrichment analysis of “common” gene set were listed in Figures 3 and S1, respectively.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Translational Medicine and Key Laboratory of Arrhythmias of The Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China.

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.

No MeSH data available.


Related in: MedlinePlus