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Decreased expression of the translation factor eIF3e induces senescence in breast cancer cells via suppression of PARP1 and activation of mTORC1.

Christelle Morris, Sébastien Durand, and Pierre Jalinot (2021)

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.

 
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