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 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. 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.
Original language | English (US) |
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Pages (from-to) | 985-1003.e7 |
Journal | Cancer Cell |
Volume | 33 |
Issue number | 6 |
DOIs | |
State | Published - Jun 11 2018 |
Externally published | Yes |
Keywords
- Ca signaling
- NRF2
- TRP channel
- TRPA1
- anchorage-independent growth
- anti-apoptosis
- chemotherapy resistance
- oxidative stress
- tumor progression
ASJC Scopus subject areas
- Oncology
- Cancer Research