TRPA1, sometimes called the “wasabi receptor” is responsible for the sensation that gets triggered when you take a bite of wasabi or spicy mustard. More generally, TRPA1 is known to be a sensor for environmental irritants and plays roles in detecting sensations such as pain and cold, and in airway inflammation conditions like asthma. Though it is known that certain cancers express unusually high levels of TRPA1, why this is has remained unclear.
According to a study published this week in Cancer Cell, Harvard Medical School researchers have now shown that tumor cells use TRPA1 as a defense mechanism against reactive oxygen species.
Metabolic processes that use oxygen can cause a buildup of ROS, which is highly reactive and can be harmful to cellular structures. For rapidly dividing cancer cells, this can become a major blocker of proliferation.
Previous work done by the HMS researchers, had shown that ROS can activate TRPA1 in neurons. For the current study, human breast and lung cancer were grown into 3-D spheroids that mimic a tumor’s natural structure. They found ROS levels were substantially higher within the spheroids compared to the surface, but that this had little effect on cell survival. However, blocking of TRPA1 led to death of the cancer cells in response to ROS and the cells were cleared within days.
The team found that an influx of calcium ions through TRPA1 triggers a cascade of cellular signals that suppresses programmed cell death. Furthermore, TRPA1 expression was found to be induced by NRF2, a transcription factor that controls production of antioxidants. Exposure to high levels of ROS appeared to cause the cancer cells to rely on NRF2 to activate antioxidant production and prevent apoptosis through TRPA1.
"The cellular program that increases production of antioxidants also simultaneously activates this unique TRPA1-dependent defense mechanism, which allows cancer cells to tolerate enhanced levels of ROS," said Takahashi, who is lead author on the study. "These two very different pathways work together to help tumors survive and adapt to oxidative stress."
In mice with transplanted human breast cancer tumors, blocking TRPA1 with drugs slowed tumor growth and increased the sensitivity of cancer cells to chemotherapy. Combined treatment of TRPA1 blockers and chemotherapy caused a significant reduction in tumor size.
Experiments are currently underway to find a small molecule drug that can safely inhibit TRPA1. This study adds to a growing body of research indicating that cancers can exploit antioxidants for their survival.