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

Publication date: Available online 24 May 2018
Source:Cancer Cell
Author(s): 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
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 Ca²⁺-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 Ca²⁺-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.

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Teaser

Takahashi et al. show that TRPA1, a neuronal redox-sensing Ca²⁺-influx channel overexpressed in human cancer, upregulates Ca²⁺-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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