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Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy

Author

Listed:
  • Susan E. Logue

    (National University of Ireland Galway
    National University of Ireland Galway)

  • Eoghan P. McGrath

    (National University of Ireland Galway
    National University of Ireland Galway)

  • Patricia Cleary

    (National University of Ireland Galway
    National University of Ireland Galway)

  • Stephanie Greene

    (Fosun Orinove PharmaTech Inc.)

  • Katarzyna Mnich

    (National University of Ireland Galway
    National University of Ireland Galway)

  • Aitor Almanza

    (National University of Ireland Galway
    National University of Ireland Galway)

  • Eric Chevet

    (Université de Rennes 1
    Centre de Lutte Contre le Cancer Eugène Marquis)

  • Róisín M. Dwyer

    (National University of Ireland Galway)

  • Anup Oommen

    (National University of Ireland Galway)

  • Patrick Legembre

    (Université de Rennes 1
    Centre de Lutte Contre le Cancer Eugène Marquis)

  • Florence Godey

    (Université de Rennes 1
    Centre de Lutte Contre le Cancer Eugène Marquis)

  • Emma C. Madden

    (National University of Ireland Galway
    National University of Ireland Galway)

  • Brian Leuzzi

    (National University of Ireland Galway
    National University of Ireland Galway)

  • Joanna Obacz

    (Université de Rennes 1
    Centre de Lutte Contre le Cancer Eugène Marquis)

  • Qingping Zeng

    (Fosun Orinove PharmaTech Inc.)

  • John B. Patterson

    (Fosun Orinove PharmaTech Inc.)

  • Richard Jäger

    (University of Applied Sciences, Department of Natural Sciences)

  • Adrienne M. Gorman

    (National University of Ireland Galway
    National University of Ireland Galway)

  • Afshin Samali

    (National University of Ireland Galway
    National University of Ireland Galway)

Abstract

Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.

Suggested Citation

  • Susan E. Logue & Eoghan P. McGrath & Patricia Cleary & Stephanie Greene & Katarzyna Mnich & Aitor Almanza & Eric Chevet & Róisín M. Dwyer & Anup Oommen & Patrick Legembre & Florence Godey & Emma C. Ma, 2018. "Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05763-8
    DOI: 10.1038/s41467-018-05763-8
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    Cited by:

    1. Michael J. P. Crowley & Bhavneet Bhinder & Geoffrey J. Markowitz & Mitchell Martin & Akanksha Verma & Tito A. Sandoval & Chang-Suk Chae & Shira Yomtoubian & Yang Hu & Sahil Chopra & Diamile A. Tavarez, 2023. "Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Aitor Almanza & Katarzyna Mnich & Arnaud Blomme & Claire M. Robinson & Giovanny Rodriguez-Blanco & Sylwia Kierszniowska & Eoghan P. McGrath & Matthieu Gallo & Eleftherios Pilalis & Johannes V. Swinnen, 2022. "Regulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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