Abstract
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.
Highlights
Cellular senescence is a major driver of various age-related diseases, including cancer
EIF3e silencing results in homologous recombination (HR) defect in breast cancer cells (Supplementary Figure 1), we found that these eIF3e-depleted cells were not sensitive to veliparib treatment, in contrast to BRCA1-depleted cells (Figure 1A)
These findings indicate that cancer cells with low eIF3e amounts are refractory to PARP inhibitors (PARPi), suggesting that assessing eIF3e levels in tumors could be informative to predict the clinical response to PARPi
Summary
Cellular senescence is a major driver of various age-related diseases, including cancer. This complex cell state operates as a barrier against cancer by arresting proliferation of cancerous cells, but it favors a protumorigenic environment by inducing the secretion of numerous factors collectively referred to as the senescence-associated secretory phenotype (SASP) [1,2,3]. Upon DNA binding, PARP1 rapidly synthesizes and attaches poly(ADP-ribose) (PAR) polymers onto itself and various target proteins. These PAR modifications enable the recruitment of repair proteins. PARP inhibitors (PARPi) are used in clinic to treat various cancers defective in DNA repair via homologous recombination (HR), those due to BRCA1/2 loss of functions [11,12,13]
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