Genome-wide synthetic lethal screen unveils novel CAIX – NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA704708 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13780413.fastq.gz | Fastqsanger.gz | |||
| SRR13780414.fastq.gz | Fastqsanger.gz | |||
| SRR13780415.fastq.gz | Fastqsanger.gz | |||
| SRR13780416.fastq.gz | Fastqsanger.gz | |||
| SRR13780417.fastq.gz | Fastqsanger.gz |
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Project description:Tumor cells increase glutamate release through the cystine/glutamate transporter xCT to balance oxidative homeostasis in tumor cells and promote tumor progression. Here, we demonstrated that although inhibition of xCT either by pharmacological inhibitor (sulfasalazine, SAS), approved by FDA for inflammatory diseases, or genetic knockdown induced ROS-related death in melanoma cells. Taken together, our results reveal that inhibition of xCT by SAS is a promising therapeutic strategy for melanoma.
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Project description: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.
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