1. XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells.
- Author
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Zou T, Zhou M, Gupta A, Zhuang P, Fishbein AR, Wei HY, Capcha-Rodriguez D, Zhang Z, Cherniack AD, and Meyerson M
- Subjects
- Interferon-beta, Exoribonucleases metabolism, Protein Kinases, Interferons, Neoplasms genetics
- Abstract
Emerging data suggest that induction of viral mimicry responses through activation of double-stranded RNA (dsRNA) sensors in cancer cells is a promising therapeutic strategy. One approach to induce viral mimicry is to target molecular regulators of dsRNA sensing pathways. Here, we show that the exoribonuclease XRN1 is a negative regulator of the dsRNA sensor protein kinase R (PKR) in cancer cells with high interferon-stimulated gene expression. XRN1 deletion causes PKR pathway activation and consequent cancer cell lethality. Disruption of interferon signaling with the JAK1/2 inhibitor ruxolitinib can decrease cellular PKR levels and rescue sensitivity to XRN1 deletion. Conversely, interferon-β stimulation can increase PKR levels and induce sensitivity to XRN1 inactivation. Lastly, XRN1 deletion causes accumulation of endogenous complementary sense/anti-sense RNAs, which may represent candidate PKR ligands. Our data demonstrate how XRN1 regulates PKR and how this interaction creates a vulnerability in cancer cells with an activated interferon cell state., Competing Interests: Declaration of interests T.Z.’s spouse is an employee of and holds equity in HiFiBiO Therapeutics and holds equity in Novartis. M.Z. is now an employee of Bayer Pharmaceuticals in Cambridge, MA. A.D.C. receives research funding from Bayer Pharmaceuticals and has a consulting role for BirdsEye Bio. M.M. receives research funding from Bayer Pharmaceuticals and Janssen Pharmaceuticals; has a consulting role and equity with Delve Bio, Interline, and Isabl; and receives patent royalties on intellectual property from The Broad Institute of Harvard and MIT and Dana-Farber Cancer Institute licensed to Bayer and LabCorp, respectively., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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