Annuaire
Decreased expression of the translation factor eIF3e induces senescence in breast cancer cells via suppression of PARP1 and activation of mTORC1.
Oncotarget, 12(7):649-664.
Altered expression of the translation factor eIF3e is associated with breastcancer occurrence. We have previously shown that eIF3e deficiency leads to animpaired DNA damage response with a marked decrease in DNA repair by homologousrecombination. Here, we explored the possibility to exploit this DNA repairdefect in targeted cancer therapy using PARP inhibitors. Surprisingly,eIF3e-deficient breast cancer cells are resistant to these drugs, in contrast toBRCA1-deficient cells. Studying this, we found that eIF3e-depleted cellssynthesize lowered amounts of PARP1 protein, due to a weakened translation of thecorresponding mRNA, associated with a strong decrease in cellularpoly(ADP-ribosyl)ation. Additionally, we discovered that the mTORC1 signalingpathway is aberrantly activated in response to eIF3e suppression. Together, thesePARP1 and mTORC1 dysfunctions upon eIF3e depletion are causally linked toinduction of cellular senescence associated with a pro-inflammatory secretoryphenotype. This study provides mechanistic insights into how eIF3e protectsagainst breast cancer, with potential novel cancer therapeutic opportunities.While PARP inhibitors appear as inappropriate drugs for eIF3e-deficient breasttumors, our findings suggest that such cancers may benefit from senolytic drugsor mTORC1 inhibitors.
Actions sur le document
