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miR-217 Regulates Normal and Tumor Cell Fate Following Induction of Endoplasmic Reticulum Stress.
Neekkan Dey1, Costas Koumenis2, Davide Ruggero3
1Department of Biochemistry, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
Molecular Cancer Research : MCR
|January 18, 2024
Summary
Tumor cells adapt to nutrient scarcity via the unfolded protein response (UPR). PERK activation induces miR-217, which limits survival miRNA miR-211, promoting apoptosis and cancer cell fate.
Area of Science:
- Cancer Biology
- Molecular Biology
- Cellular Stress Response
Background:
- Cancer cells face nutrient scarcity in tumors, typically inducing growth arrest or apoptosis.
- Tumor cells exploit survival pathways, like the unfolded protein response (UPR), to adapt to stress.
- The PERK (protein kinase R-like endoplasmic reticulum kinase) pathway is a key UPR effector involved in tumor cell adaptation.
Purpose of the Study:
- To identify novel microRNAs (miRNAs) regulated by PERK during prolonged endoplasmic reticulum (ER) stress.
- To elucidate the role of the identified miRNA, miR-217, in cancer cell fate determination under stress.
- To investigate the relationship between miR-217, miR-211, and their targets in the context of ER stress adaptation or apoptosis.
Main Methods:
- Analysis of miRNA expression under prolonged ER stress.
- Identification of PERK-responsive miRNAs.
- Target prediction and validation for miR-217.
- Assessment of cell fate (adaptation vs. apoptosis) in response to miR-217 modulation.
Main Results:
- A novel PERK-responsive miRNA, miR-217, was identified with increased expression under prolonged ER stress.
- Key targets of miR-217 include TRPM1 (host gene for miR-211) and EZH2.
- miR-217 expression is crucial for the downregulation of miR-211 during prolonged ER stress.
- miR-217 modulates cell fate, promoting commitment to apoptosis rather than adaptation.
Conclusions:
- PERK-dependent induction of miR-217 plays a critical role in managing cell fate under ER stress.
- miR-217 limits the accumulation and function of the prosurvival miRNA, miR-211.
- This regulatory axis established by miR-217 is essential for promoting apoptosis in cancer cells experiencing nutrient deprivation.
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