TRPA1 is upregulated in tumors and increases Ca2+ levels to enhance cell survival in response to ROS.

  • Major finding: TRPA1 is upregulated in tumors and increases Ca2+ levels to enhance cell survival in response to ROS.

  • Mechanism: TRPA1 upregulates Ca2+-dependent antiapoptotic signaling pathways to protect against oxidative stress.

  • Impact: TRPA1 may be a potential therapeutic target to enhance chemosensitivity in patients with cancer.

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Tumor cells require oxidative-stress defense programs to protect against reactive oxygen species (ROS) that promote apoptosis. Canonical ROS-neutralizing programs, including the KEAP1–NRF2 pathway, have been well characterized in tumorigenesis but may not be amenable to therapeutic targeting because of the increase in oxidative stress in normal tissues. Takahashi and colleagues identified a noncanonical oxidative stress defense mechanism mediated by TRPA1, a neuronal redox-sensing Ca2+-influx channel. Analysis of data from The Cancer Genome Atlas revealed that TRPA1 is overexpressed in multiple tumor types including invasive ductal breast cancer, kidney renal clear cell carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, and malignant peripheral nerve sheath tumors. TRPA1 expression increased the intracellular Ca2+ concentration and enhanced cell survival in response to the ROS H2O2, indicating that TRPA1-mediated Ca2+ influx may protect cancer cells against oxidative stress. In 3-D tumor spheroids, TRPA1 expression prevented apoptosis of the inner cells in the spheroid. The inner cells had higher levels of ROS, but TRPA1 expression did not reduce ROS levels; instead, the TRPA1-mediated Ca2+ influx promoted survival of the ROS-high cells. Mechanistically, TRPA1 was upregulated by the transcription factor NRF2 and protected against oxidative stress via upregulation of Ca2+-dependent antiapoptotic signaling pathways. Further, the TRPA1-mediated Ca2+ influx reduced the sensitivity of tumor cells to platinum-based chemotherapies. In vivo, TRPA1 inhibition suppressed the growth of breast cancer xenografts and conferred increased sensitivity to carboplatin. In patients with lung or breast cancer, high TRPA1 expression was associated with poorer overall survival, suggesting the potential for therapeutic targeting of TRPA1. Taken together, these findings elucidate a TRPA1-mediated noncanonical oxidative stress defense mechanism that promotes tumor growth and chemoresistance.

Takahashi N, Chen HY, Harris IS, Stover DG, Selfors LM, Bronson RT, et al. Cancer cells co-opt the neuronal redox-sensing channel TRPA1 to promote oxidative-stress tolerance. Cancer Cell 2018;33:985–1003.e7.

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