Therapeutic targeting of the PI4K2A/PKR lysosome network is critical for misfolded protein clearance and survival in cancer cells

Apar Pataer,Mourad Majidi,Neil R Cashman,Jack A Roth,Ruping Shao,Bingliang Fang,Stephen G Swisher,Steven H Lin,Bulent Ozpolat,Ara A Vaporciyan,Ignacio I Wistuba,Mien-Chie Hung,Nashwa N Kabil,Steven S Plotkin,Jing Wang,Charles E Samuel

doi:10.1038/s41388-019-1010-4

Abstract

The role of RNA-dependent protein kinase R (PKR) and its association with misfolded protein expression in cancer cells are unclear. Herein we report that PKR regulates misfolded protein clearance by preventing it release through exosomes and promoting lysosomal degradation of misfolded prion proteins in cancer cells. We demonstrated that PKR contributes to the lysosome function and regulates misfolded prion protein clearance. We hypothesized that PKR-associated lysosome function is critical for cancer but not normal cell survival, representing an effective approach for highly targeted cancer therapy. In screening a compound library, we identified two PKR-associated compounds 1 and 2 (Pac 1 and 2) did not affect normal cells but selectively induced cell death in cancer cells depending on their PKR expression status. Pac 1 significantly inhibited the growth of human lung and breast xenograft tumors in mice with no toxicity. Pac 1 binds to PI4K2A and disrupts the PKR/PI4K2A-associated lysosome complex, contributing to destabilization of cancer cell lysosomes and triggering cell death. We observed that PKR and PI4K2A play significant prognostic roles in breast cancer patients. These results demonstrate that targeting of a PI4K2A/PKR lysosome complex may be an effective approach for cancer therapy.

Highlights

Researchers suggested that cancer cells depend on lysosome function for survival, as lysosomes eliminate abnormal proteins [1, 2]
To investigate the role of protein kinase R (PKR) in clearance of misfolded proteins in cancer cells, we developed antibody specific for misfolded prion protein (PrP)
Native and misfolded PrPs were expressed in all cancer cell lines examined but not in normal human bronchial epithelial (HBE) cells (Fig. 1a, b)

Summary

Introduction

Researchers suggested that cancer cells depend on lysosome function for survival, as lysosomes eliminate abnormal proteins [1, 2]. 11 Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA many diseases, including cancer, Alzheimer disease, Parkinson disease, Huntington disease, type 2 diabetes mellitus, inherited cataracts, atherosclerosis, hemodialysisrelated disorders, and short-chain amyloidosis [6,7,8]. Cancer cells may produce more misfolded proteins than normal cells do because of their high mutation rates, high metabolic demand, rapid growth, and aberrant glycosylation and the failure of host defense/clearance mechanisms [9,10,11,12]. Increasing evidence demonstrates that high levels of expression of misfolded proteins or RNA-dependent protein kinase R (PKR) are associated with the development of neurodegenerative diseases, such as Alzheimer, Parkinson, and Huntington disease [13,14,15,16,17]. Further investigation of the role of PKR and its association with misfolded protein clearance in cancer is warranted

Methods

Results

Conclusion