Iron-(Fe3+) dependent reactivation of telomerase drives colorectal cancers
Menée à l'aide de lignées cellulaires, d'organoïdes, de xénogreffes sur des modèles murins et d'échantillons tumoraux issus de patients atteints d'un cancer colorectal, cette étude met en évidence un mécanisme par lequel l'ion ferrique Fe3+, en réactivant la télomérase, favorise la carcinogenèse colorectale
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.
Cancer Discovery 2023