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

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

    Research output: Contribution to journalArticlepeer-review

    17 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)801-813
    Number of pages13
    JournalOncogene
    Volume39
    Issue number4
    DOIs
    StatePublished - Jan 23 2020

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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