Journal Article

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

Moiso, Enrico, Kopecka, Joanna, Rubinstein, Menachem, Buondonno, Ilaria, Provero, Paolo, Riganti, Chiara, Salaroglio, Iris C., Panada, Elisa

2017

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adaptation / Animals / Antioxidants / Apoptosis / Apoptosis - drug effects / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cancer therapies / Cell culture / Cell death / Cell Death - drug effects / Cell Death - genetics / Cell growth / Chemoresistance / Chemotherapy / Cloning / Colonic Neoplasms - drug therapy / Colonic Neoplasms - genetics / Colonic Neoplasms - pathology / Colorectal cancer / Doxorubicin - administration & dosage / Drug development / Drug Resistance, Neoplasm - genetics / eIF-2 Kinase - antagonists & inhibitors / eIF-2 Kinase - genetics / Endoplasmic reticulum / Endoplasmic reticulum stress / Endoplasmic Reticulum Stress - drug effects / Enzymes / Eukaryotic translation initiation factor-2α kinase 3/protein kinase RNA-like endoplasmic reticulum kinase / Homeostasis / HT29 Cells / Humans / Hypoxia / Kinases / Membrane proteins / Mice / Multidrug resistance / Multidrug resistance related protein 1 / Multidrug Resistance-Associated Proteins - genetics / Multidrug resistant organisms / NF-E2-Related Factor 2 - genetics / Oncology / Penicillin / Protein folding / Protein kinase / Protein transport / Proteins / Radiation therapy / Radiotherapy / Ribonucleic acid / RNA / Signal Transduction - drug effects / Stress response / Survival / Transcription / Transcription factors / Tumor cells / Tumors / Unfolded protein response / Unfolded Protein Response - genetics / Xenograft Model Antitumor Assays / Xenografts