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

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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.

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APA

Takahashi, N., Chen, H. Y., Harris, I. S., Stover, D. G., Selfors, L. M., Bronson, R. T., … Brugge, J. S. (2018). Cancer Cells Co-opt the Neuronal Redox-Sensing Channel TRPA1 to Promote Oxidative-Stress Tolerance. Cancer Cell, 33(6), 985-1003.e7. https://doi.org/10.1016/j.ccell.2018.05.001

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