ABSTRACT
Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA-RNA-binding protein complex LOC-DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between cancer and immune cells, intensifying cancer aggressiveness. Targeting this complex with blood-brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding cancer cell survival and stem-like properties. Focusing on RNA-RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body.
Subject(s)
Brain Neoplasms , Glioblastoma , Isocitrate Dehydrogenase , RNA-Binding Proteins , Tumor Microenvironment , Glioblastoma/pathology , Glioblastoma/genetics , Glioblastoma/metabolism , Glioblastoma/drug therapy , Humans , Brain Neoplasms/pathology , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Brain Neoplasms/drug therapy , Animals , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Cell Line, Tumor , Mice , Mutation , Antineoplastic Agents/pharmacology , Xenograft Model Antitumor Assays , Cell Proliferation , Gene Expression Regulation, NeoplasticABSTRACT
Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer (CRC) samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by re-activating the dormant human-reverse-transcriptase (hTERT) subunit of telomerase holoenzyme in an iron-(Fe3+)-dependent-manner and thereby drives CRCs. Chemical genetic screens combined with isothermal-dose response fingerprinting and mass-spectrometry identified a small molecule SP2509, that specifically inhibits Pirin-mediated hTERT reactivation in CRCs by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat, and increased incidence of CRCs. Small molecules like SP2509 represent a novel modality to target telomerase that acts as driver of 90% human cancers and is yet to be targeted in clinic.
