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Downregulation of E2F1 during ER stress is required to induce apoptosis
Vittoria Pagliarini1, Paola Giglio1, Paolo Bernardoni1
1National Institute for Infectious Disease 'L. Spallanzani' IRCCS, 00149 Rome, Italy.
Abstract:
The endoplasmic reticulum (ER) has recently emerged as an alternative target to induce cell death in tumours, because prolonged ER stress results in the induction of apoptosis even in chemoresistant transformed cells. Here, we show that the DNA-damage-responsive pro-apoptotic factor E2F1 is unexpectedly downregulated during the ER stress-mediated apoptotic programme. E2F1 decline is a late event during the ER response and is mediated by the two unfolded protein response (UPR) sensors ATF6 and IRE1 (also known as ERN1). Whereas ATF6 directly interacts with the E2F1 promoter, IRE1 requires the involvement of the known E2F1 modulator E2F7, through the activation of its main target Xbp-1. Importantly, inhibition of the E2F1 decrease prevents ER-stress-induced apoptosis, whereas E2F1 knockdown efficiently sensitises cells to ER stress-dependent apoptosis, leading to the upregulation of two main factors in the UPR pro-apoptotic execution phase, Puma and Noxa (also known as BBC3 and PMAIP1, respectively). Our results point to a novel key role of E2F1 in the cell survival/death decision under ER stress, and unveil E2F1 inactivation as a valuable novel potential therapeutic strategy to increase the response of tumour cells to ER stress-based anticancer treatments.
Insights
Endoplasmic reticulum (ER) stress induces apoptosis in cancer cells. Researchers found that decreasing the DNA-damage factor E2F1 enhances ER stress-induced cell death, suggesting a new therapeutic strategy.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- The endoplasmic reticulum (ER) is a potential target for cancer therapy due to its role in apoptosis induction, even in chemoresistant cells.
- Prolonged ER stress triggers apoptosis, offering a therapeutic avenue for cancer treatment.
Purpose of the Study:
- To investigate the role of the DNA-damage-responsive factor E2F1 in ER stress-mediated apoptosis.
- To explore the therapeutic potential of targeting E2F1 in ER stress-based cancer treatments.
Main Methods:
- Investigated E2F1 expression during ER stress-induced apoptosis.
- Utilized ATF6 and IRE1 (ERN1) pathways to elucidate E2F1 regulation.
- Examined the impact of E2F1 modulation on ER stress-induced apoptosis and UPR factors (Puma, Noxa).
Main Results:
- E2F1 is unexpectedly downregulated during ER stress-mediated apoptosis via ATF6 and IRE1 pathways.
- ATF6 directly interacts with the E2F1 promoter, while IRE1 involves E2F7 and Xbp-1.
- Inhibiting E2F1 decline prevents apoptosis, whereas E2F1 knockdown sensitizes cells to ER stress-induced apoptosis, upregulating Puma and Noxa.
Conclusions:
- E2F1 plays a critical role in the cell survival/death decision during ER stress.
- E2F1 inactivation represents a novel therapeutic strategy to enhance tumor cell response to ER stress-based anticancer treatments.
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