Journal
CANCER CELL
Volume 33, Issue 6, Pages 985-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.05.001
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Funding
- Susan G. Komen for the Cure Foundation [SAC170002]
- Breast Cancer Research Foundation
- CCSG grant [CA016672, SAC110052, BCRF-16-109]
- ROADS Program by F. Hoffmann-La Roche Ltd
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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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