Ribosomal protein S11 influences glioma response to TOP2 poisons
Chidiebere U Awah1, Li Chen1, Mukesh Bansal2
1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States.
Abstract:
Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We and others had shown that a subset of glioblastomas, the most malignant of all primary brain tumors in adults, is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, and 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 led to resistance to etoposide and doxorubicin and impaired the induction of proapoptotic gene APAF1 following treatment. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from gliomas and multiple other cancers.
Insights
Topoisomerase II (TOP2) poisons are common cancer drugs. This study identified ribosomal protein subunits RPS11, 16, and 18 as potential biomarkers for predicting patient response to TOP2 poison chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Topoisomerase II (TOP2) poisons are a widely used class of chemotherapeutics for cancer treatment.
- A subset of glioblastomas, a highly malignant primary brain tumor, demonstrates sensitivity to TOP2 poisons.
Purpose of the Study:
- To identify genes conferring susceptibility to TOP2 poisons in gliomas.
- To discover potential biomarkers for predicting patient response to TOP2 poison therapy.
Main Methods:
- Genome-scale CRISPR knockout screening was employed using etoposide (a TOP2 poison).
- CRISPR hits were overlapped with gene expression data correlating with drug susceptibility across glioma cell lines.
Main Results:
- Genes involved in protein synthesis and DNA damage pathways were linked to etoposide susceptibility.
- Ribosomal protein subunits RPS11, RPS16, and RPS18 were identified as putative biomarkers for TOP2 poison response.
- Loss of RPS11 conferred resistance to etoposide and doxorubicin and reduced APAF1 induction.
- Expression of these ribosomal subunits correlated with TOP2 poison susceptibility in glioma and other cancer cell lines.
Conclusions:
- Ribosomal protein subunits RPS11, 16, and 18 may serve as predictive biomarkers for TOP2 poison efficacy in gliomas and other cancers.
- Understanding the role of protein synthesis in drug response can inform future therapeutic strategies.
