@article{6b197acb28034b37912a6d7461666ef6,
title = "Cancer Cells Co-opt the Neuronal Redox-Sensing Channel TRPA1 to Promote Oxidative-Stress Tolerance",
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.",
keywords = "Ca signaling, NRF2, TRP channel, TRPA1, anchorage-independent growth, anti-apoptosis, chemotherapy resistance, oxidative stress, tumor progression",
author = "Nobuaki Takahashi and Chen, {Hsing Yu} and Harris, {Isaac S.} and Stover, {Daniel G.} and Selfors, {Laura M.} and Bronson, {Roderick T.} and Thomas Deraedt and Karen Cichowski and Welm, {Alana L.} and Yasuo Mori and Mills, {Gordon B.} and Brugge, {Joan S.}",
note = "Funding Information: J.S.B. receives funding from F. Hoffmann-La Roche Ltd . G.B.M. holds advisory positions on SAB for AstraZeneca and Immunomet and has received funding support from Karus , Pfizer , Tesaro , AstraZeneca , and Immunomet . This work is related to a patent application: PCT/US18/20937 titled “Methods of Use for TRP Channel Antagonist-Based Combination Cancer Therapies”. Funding Information: We thank Patricia Cho, Xiangkun Han, Jonathan Coloff, Hendrik Johannes Kuiken, Carman Li, Grace Gao, Tony Yeung, Satoshi Hamano, and Astrid Ruefli-Brasse for reagents and/or helpful discussions and Angie Martinez Gakidis for scientific editing. Image analysis and cell viability assay were performed at The Nikon Imaging Center and ICCB-Longwood Screening Facility at Harvard Medical School. This research was supported by the Susan G. Komen for the Cure Foundation ( SAC170002 , J.S.B.), the Breast Cancer Research Foundation (J.S.B.), CCSG grant CA016672 (G.B.M.), SAC110052 (G.B.M.), BCRF-16-109 (G.B.M.), and by funding from the ROADS Program funded by F. Hoffmann-La Roche Ltd to J.S.B. Funding Information: J.S.B. receives funding from F. Hoffmann-La Roche Ltd. G.B.M. holds advisory positions on SAB for AstraZeneca and Immunomet and has received funding support from Karus, Pfizer, Tesaro, AstraZeneca, and Immunomet. This work is related to a patent application: PCT/US18/20937 titled ?Methods of Use for TRP Channel Antagonist-Based Combination Cancer Therapies?. Funding Information: J.S.B. receives funding from F. Hoffmann-La Roche Ltd. G.B.M. holds advisory positions on SAB for AstraZeneca and Immunomet and has received funding support from Karus, Pfizer, Tesaro, AstraZeneca, and Immunomet. This work is related to a patent application: PCT/US18/20937 titled “Methods of Use for TRP Channel Antagonist-Based Combination Cancer Therapies”. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = jun,
day = "11",
doi = "10.1016/j.ccell.2018.05.001",
language = "English (US)",
volume = "33",
pages = "985--1003.e7",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}