Abstract 5478: The TRPA1 Ca2+-permeable channel mediates a non-canonical redox adaptation in cancer cells

Abstract

Abstract Generation of reactive oxygen species (ROS), a natural byproduct of oxygen metabolism, occurs in all aerobic organisms at a controlled rate. Cancer cells are subjected to numerous cellular insults, including dysregulated oncogenes and dissociation from their natural extracellular matrix (ECM) niches, leading to the generation of high levels of ROS. Although cancer cells possess enhanced canonical antioxidant programs that neutralize ROS, they nevertheless exhibit prominent ROS levels in response to these insults, suggesting the existence of additional programs that allow cancer cells to tolerate elevated ROS. In this study, we provide evidence for an unconventional mechanism for redox adaptation involving the ROS-activated, Ca2+-permeable TRPA1 channel, which normally functions as an irritant receptor in sensory neurons but is highly upregulated in breast, lung, malignant neural sheath, and other tumors. We found that TRPA1 overexpression enhances survival and proliferation of MCF-10A cells under conditions of matrix-detachment and this effect was dependent on TRPA1 activation by ROS generated as loss of matrix anchorage. In MCF-10A acini, TRPA1 expression induced Ca2+ entry in ECM-deprived cells in the luminal space and promoted their survival and proliferation. Conversely, TRPA1 knockdown inhibited Ca2+ responses to ROS generated through ECM detachment and induced clearance of cells from the luminal space in breast cancer spheroids. TRPA1 was also activated by ROS-inducing chemotherapies and drove chemoresistance in breast, lung and malignant peripheral nerve sheath tumor cells, and its downregulation suppressed breast xenograft tumor growth and enhanced chemosensitivity. TRPA1 mediated these effects independent of antioxidant responses, but through activation of cellular survival and anti-apoptotic programs involving the RAS-ERK/AKT/mTOR pathways. Together, our findings describe an unexpected mechanism whereby cancer cells co-opt the neuronal TRPA1 channel in order to adapt to oxidative environments. This TRPA1-induced response is distinct from canonical redox adaptation mechanisms that rely on antioxidant program. As TRPA1 inhibitors are currently in clinical trials for pain and respiratory therapies, these studies raise the possibility of using these inhibitors as therapeutic chemosensitizers in TRPA1-enriched tumors. Citation Format: Nobuaki Takahashi, Hsing-Yu Chen, Isaac Harris, Daniel Stover, Roderick Bronson, Thomas Deraedt, Karen Cichowski, Alana Welm, Gordon Mills, Joan Brugge. The TRPA1 Ca2+-permeable channel mediates a non-canonical redox adaptation in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5478. doi:10.1158/1538-7445.AM2017-5478