Decreased expression of the translation factor eIF3e induces senescence in breast cancer cells via suppression of PARP1 and activation of mTORC1
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Christelle Morris1, Sébastien Durand1,2 and Pierre Jalinot1
1 University Lyon, ENS de Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5239, INSERM U1210, LBMC, Lyon, France
2 University Lyon, Cancer Research Center of Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS UMR 5286, Centre Léon Bérard, Cancer Cell Plasticity Department, Equipe 'Transcriptome Diversity in Stem Cells', Lyon, France
Keywords: breast cancer; senescence-associated secretory phenotype; eIF3; PARP1; mTORC1
Received: November 28, 2020 Accepted: March 08, 2021 Published: March 30, 2021
Altered expression of the translation factor eIF3e is associated with breast cancer occurrence. We have previously shown that eIF3e deficiency leads to an impaired DNA damage response with a marked decrease in DNA repair by homologous recombination. Here, we explored the possibility to exploit this DNA repair defect in targeted cancer therapy using PARP inhibitors. Surprisingly, eIF3e-deficient breast cancer cells are resistant to these drugs, in contrast to BRCA1-deficient cells. Studying this, we found that eIF3e-depleted cells synthesize lowered amounts of PARP1 protein, due to a weakened translation of the corresponding mRNA, associated with a strong decrease in cellular poly(ADP-ribosyl)ation. Additionally, we discovered that the mTORC1 signaling pathway is aberrantly activated in response to eIF3e suppression. Together, these PARP1 and mTORC1 dysfunctions upon eIF3e depletion are causally linked to induction of cellular senescence associated with a pro-inflammatory secretory phenotype. This study provides mechanistic insights into how eIF3e protects against breast cancer, with potential novel cancer therapeutic opportunities. While PARP inhibitors appear as inappropriate drugs for eIF3e-deficient breast tumors, our findings suggest that such cancers may benefit from senolytic drugs or mTORC1 inhibitors.
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