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PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy.
- Source :
- Molecular Cancer; 5/12/2017, Vol. 16, p1-13, 13p, 6 Graphs
- Publication Year :
- 2017
-
Abstract
- Background: Nutrient deprivation, hypoxia, radiotherapy and chemotherapy induce endoplasmic reticulum (ER) stress, which activates the so-called unfolded protein response (UPR). Extensive and acute ER stress directs the UPR towards activation of death-triggering pathways. Cancer cells are selected to resist mild and prolonged ER stress by activating pro-survival UPR. We recently found that drug-resistant tumor cells are simultaneously resistant to ER stress-triggered cell death. It is not known if cancer cells adapted to ER stressing conditions acquire a chemoresistant phenotype. Methods: To investigate this issue, we generated human cancer cells clones with acquired resistance to ER stress from ER stress-sensitive and chemosensitive cells. Results: ER stress-resistant cells were cross-resistant to multiple chemotherapeutic drugs: such multidrug resistance (MDR) was due to the overexpression of the plasma-membrane transporter MDR related protein 1 (MRP1). Gene profiling analysis unveiled that cells with acquired resistance to ER stress and chemotherapy share higher expression of the UPR sensor protein kinase RNA-like endoplasmic reticulum kinase (PERK), which mediated the erythroid-derived 2-like 2 (Nrf2)-driven transcription of MRP1. Disrupting PERK/Nrf2 axis reversed at the same time resistance to ER stress and chemotherapy. The inducible silencing of PERK reduced tumor growth and restored chemosensitivity in resistant tumor xenografts. Conclusions: Our work demonstrates for the first time that the adaptation to ER stress in cancer cells produces a MDR phenotype. The PERK/Nrf2/MRP1 axis is responsible for the resistance to ER stress and chemotherapy, and may represent a good therapeutic target in aggressive and resistant tumors. [ABSTRACT FROM AUTHOR]
- Subjects :
- PROTEIN kinases
ENDOPLASMIC reticulum
CELL death
CANCER chemotherapy
CANCER cells
Subjects
Details
- Language :
- English
- ISSN :
- 14764598
- Volume :
- 16
- Database :
- Complementary Index
- Journal :
- Molecular Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 123098608
- Full Text :
- https://doi.org/10.1186/s12943-017-0657-0