Ceftriaxone exerts antitumor effects in MYCN-driven retinoblastoma and neuroblastoma by targeting DDX3X for translation repression
Issued Date
2023-01-01
Resource Type
ISSN
15747891
eISSN
18780261
Scopus ID
2-s2.0-85178369554
Pubmed ID
37975412
Journal Title
Molecular Oncology
Rights Holder(s)
SCOPUS
Bibliographic Citation
Molecular Oncology (2023)
Suggested Citation
Chittavanich P., Saengwimol D., Roytrakul S., Rojanaporn D., Chaitankar V., Srimongkol A., Anurathapan U., Hongeng S., Kaewkhaw R. Ceftriaxone exerts antitumor effects in MYCN-driven retinoblastoma and neuroblastoma by targeting DDX3X for translation repression. Molecular Oncology (2023). doi:10.1002/1878-0261.13553 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/91422
Title
Ceftriaxone exerts antitumor effects in MYCN-driven retinoblastoma and neuroblastoma by targeting DDX3X for translation repression
Other Contributor(s)
Abstract
MYCN proto-oncogene, bHLH transcription factor (MYCN) amplification is associated with aggressive retinoblastoma (RB) and neuroblastoma (NB) cancer recurrence that is resistant to chemotherapies. Therefore, there is an urgent need to identify new therapeutic tools. This study aimed to evaluate the potential repurposing of ceftriaxone for the treatment of MYCN-amplified RB and NB, based on the clinical observations that the drug was serendipitously found to decrease the volume of the MYCN-driven RB subtype. Using patient-derived tumor organoids and tumor cell lines, we demonstrated that ceftriaxone is a potent and selective growth inhibitor targeting MYCN-driven RB and NB cells. Profiling of drug-induced transcriptomic changes, cell-cycle progression, and apoptotic death indicated cell-cycle arrest and death of drug-treated MYCN-amplified tumor cells. Drug target identification, using an affinity-based proteomic and molecular docking approach, and functional studies of the target proteins revealed that ceftriaxone targeted DEAD-box helicase 3 X-linked (DDX3X), thereby inhibiting translation in MYCN-amplified tumors but not in MYCN-nonamplified cells. The data suggest the feasibility of repurposing ceftriaxone as an anticancer drug and provide insights into the mechanism of drug action, highlighting DDX3X as a potential target for treating MYCN-driven tumors.