Language
English
Publication Date
11-8-2025
Journal
Cancers
DOI
10.3390/cancers17223604
PMID
41300971
PMCID
PMC12651708
PubMedCentral® Posted Date
11-8-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Resistance to alkylating chemotherapeutic agents such as temozolomide (TMZ) is a significant challenge in treating tumors with high MGMT expression, including MGMT-positive glioblastoma and neuroendocrine neoplasms. In this study, we investigated the effect of RNA-binding motif protein 39 (RBM39) downregulation on MGMT protein levels, based on prior observations suggesting an association between these two proteins. Pharmacological depletion or siRNA-mediated knockdown of RBM39 led to a marked reduction in MGMT protein levels in MGMT-expressing cancer cells. We further showed that dual targeting of RBM39 (using indisulam) and MGMT (with O6-benzylguanine) synergistically enhanced MGMT depletion. Functionally, combined indisulam and TMZ treatment significantly increased apoptosis and decreased clonogenic growth in neuroendocrine tumor cells. These findings identify MGMT as a downstream target of RBM39 in MGMT-expressing cancer cells and highlight the therapeutic potential of co-targeting RBM39 and MGMT to overcome resistance to alkylating chemotherapy.
Keywords
neuroendocrine neoplasms, MGMT, RBM39, temozolomide resistance, alkylating chemotherapy
Published Open-Access
yes
Recommended Citation
Khalaj, Vahid; Adams, Jack T; AghaAmiri, Solmaz; et al., "RBM39 Contributes to MGMT Maintenance in Response to Temozolomide-Induced DNA Damage" (2025). The Brown Foundation: Institute of Molecular Medicine. 44.
https://digitalcommons.library.tmc.edu/molecular_med/44