Limits...
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

Validation of microarray results by qRT-PCR for selected candidate genesThe transcriptional levels of selected 5 candidate genes upregulated (A) or downregulated (B) as shown in microarray data were validated by using qRT-PCR, respectively. Error bars represent the S.E.M. for 3 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4494968&req=5

Figure 4: Validation of microarray results by qRT-PCR for selected candidate genesThe transcriptional levels of selected 5 candidate genes upregulated (A) or downregulated (B) as shown in microarray data were validated by using qRT-PCR, respectively. Error bars represent the S.E.M. for 3 independent experiments.

Mentions: We next selected 5 genes from the top 20 upregulated or downregulated candidate list (Tables 1 and 2) for validation of their transcriptional change by qRT-PCR. Our results indicated that all the 5 genes (OSGIN1, HSPA6, DHRS2, PPP1R15A and HSPA1A) were significantly upregulated in SASP-treated PEL cells when compared with vehicle-treated cells; while another 5 genes (ASZ1, ARL4C, NREP, LGALS13, PPIA) were all significantly downregulated in SASP-treated PEL cells (Figure 4). Moreover, the altered transcriptional levels of these genes in all the 3 KSHV+ PEL cell-lines (BCBL-1, BC-1 and BCP-1) were comparable to those found in microarray data, demonstrating the credibility of our microarray analysis.


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)

Validation of microarray results by qRT-PCR for selected candidate genesThe transcriptional levels of selected 5 candidate genes upregulated (A) or downregulated (B) as shown in microarray data were validated by using qRT-PCR, respectively. Error bars represent the S.E.M. for 3 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Validation of microarray results by qRT-PCR for selected candidate genesThe transcriptional levels of selected 5 candidate genes upregulated (A) or downregulated (B) as shown in microarray data were validated by using qRT-PCR, respectively. Error bars represent the S.E.M. for 3 independent experiments.
Mentions: We next selected 5 genes from the top 20 upregulated or downregulated candidate list (Tables 1 and 2) for validation of their transcriptional change by qRT-PCR. Our results indicated that all the 5 genes (OSGIN1, HSPA6, DHRS2, PPP1R15A and HSPA1A) were significantly upregulated in SASP-treated PEL cells when compared with vehicle-treated cells; while another 5 genes (ASZ1, ARL4C, NREP, LGALS13, PPIA) were all significantly downregulated in SASP-treated PEL cells (Figure 4). Moreover, the altered transcriptional levels of these genes in all the 3 KSHV+ PEL cell-lines (BCBL-1, BC-1 and BCP-1) were comparable to those found in microarray data, demonstrating the credibility of our microarray analysis.

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