Cancer Cells Co-opt the Neuronal Redox-Sensing Channel TRPA1 to Promote Oxidative-Stress Tolerance

Nobuaki Takahashi, Hsing Yu Chen, Isaac S. Harris, Daniel G. Stover, Laura M. Selfors, Roderick T. Bronson, Thomas Deraedt, Karen Cichowski, Alana L. Welm, Yasuo Mori, Gordon B. Mills, Joan S. Brugge

    Research output: Contribution to journalArticlepeer-review

    41 Scopus citations

    Abstract

    Cancer cell survival is dependent on oxidative-stress defenses against reactive oxygen species (ROS) that accumulate during tumorigenesis. Here, we show a non-canonical oxidative-stress defense mechanism through TRPA1, a neuronal redox-sensing Ca 2+ -influx channel. In TRPA1-enriched breast and lung cancer spheroids, TRPA1 is critical for survival of inner cells that exhibit ROS accumulation. Moreover, TRPA1 promotes resistance to ROS-producing chemotherapies, and TRPA1 inhibition suppresses xenograft tumor growth and enhances chemosensitivity. TRPA1 does not affect redox status but upregulates Ca 2+ -dependent anti-apoptotic pathways. NRF2, an oxidant-defense transcription factor, directly controls TRPA1 expression, thus providing an orthogonal mechanism for protection against oxidative stress together with canonical ROS-neutralizing mechanisms. These findings reveal an oxidative-stress defense program involving TRPA1 that could be exploited for targeted cancer therapies. Takahashi et al. show that TRPA1, a neuronal redox-sensing Ca 2+ -influx channel overexpressed in human cancer, upregulates Ca 2+ -dependent anti-apoptotic pathways to promote ROS resistance. NRF2 directly controls TRPA1 expression and TRPA1 inhibition suppresses xenograft tumor growth and enhances chemosensitivity.

    Original languageEnglish (US)
    Pages (from-to)985-1003.e7
    JournalCancer Cell
    Volume33
    Issue number6
    DOIs
    StatePublished - Jun 11 2018

    Keywords

    • Ca signaling
    • NRF2
    • TRP channel
    • TRPA1
    • anchorage-independent growth
    • anti-apoptosis
    • chemotherapy resistance
    • oxidative stress
    • tumor progression

    ASJC Scopus subject areas

    • Oncology
    • Cell Biology
    • Cancer Research

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