PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy.

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.

• Authors: Iris C Salaroglio, Elisa Panada, Enrico Moiso, Ilaria Buondonno, Paolo Provero, Menachem Rubinstein, Joanna Kopecka, Chiara Riganti
• Journal: Molecular cancer (Mol Cancer) Vol. 16 Issue 1 Pg. 91 (05 12 2017) ISSN: 1476-4598 [Electronic] England
• PMID: 28499449 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Multidrug Resistance-Associated Proteins
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Doxorubicin
• EIF2AK3 protein, human
• eIF-2 Kinase
• multidrug resistance-associated protein 1

Topics

• Animals
• Apoptosis (drug effects)
• Cell Death (drug effects, genetics)
• Colonic Neoplasms (drug therapy, genetics, pathology)
• Doxorubicin (administration & dosage)
• Drug Resistance, Neoplasm (genetics)
• Endoplasmic Reticulum Stress (drug effects)
• HT29 Cells
• Humans
• Mice
• Multidrug Resistance-Associated Proteins (genetics)
• NF-E2-Related Factor 2 (genetics)
• Signal Transduction (drug effects)
• Unfolded Protein Response (genetics)
• Xenograft Model Antitumor Assays
• eIF-2 Kinase (antagonists & inhibitors, genetics)