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

被引：190

作者：

Takahashi, Nobuaki ^{[1
]}

Chen, Hsing-Yu ^{[1
]}

Harris, Isaac S. ^{[1
]}

Stover, Daniel G. ^{[1
,2
]}

Selfors, Laura M. ^{[1
]}

Bronson, Roderick T. ^{[3
]}

Deraedt, Thomas ^{[4
]}

Cichowski, Karen ^{[4
]}

Welm, Alana L. ^{[5
]}

Mori, Yasuo ^{[6
]}

Mills, Gordon B. ^{[7
]}

Brugge, Joan S. ^{[1
]}

机构：

[1] Harvard Med Sch, Ludwig Ctr Harvard, Dept Cell Biol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Harvard Med Sch, Rodent Histopathol Core, Boston, MA 02115 USA

[4] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[5] Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA

[6] Kyoto Univ, Grad Sch Engn, Dept Synthet Chem & Biol Chem, Kyoto 6158510, Japan

[7] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

来源：

CANCER CELL | 2018年 / 33卷 / 06期

关键词：

GENE-EXPRESSION; COVALENT MODIFICATION; PANCREATIC-CANCER; BREAST-CANCER; ANTIOXIDANT; ACTIVATION; RESISTANCE; SURVIVAL; GROWTH; ROS;

D O I：

10.1016/j.ccell.2018.05.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：985 / +

页数：26