MAY 24, 2018, New York — A dab too much wasabi can reduce even the most hardened of stoics to tears, thanks to loud warnings sent by the nervous system, which suspects exposure to potentially harmful chemicals. Those signals are triggered by TRPA1, a calcium channel protein sometimes referred to as the “wasabi receptor.” Many cancers, particularly those of the lung and breast, express unusually high levels of this receptor. But why they do so has been unclear.
Consider it clarified. In a study published online in Cancer Cell on May 24, a team led by Joan Brugge, co-director of the Ludwig Center at Harvard, shows that tumor cells use TRPA1 as a unique defense mechanism against reactive oxygen species (ROS), toxic byproducts of cell metabolism.
“This was quite an unexpected finding. Tumor cells appear to have co-opted this neural protein channel, which is associated with multiple types of cancer, to protect themselves against oxidative stress,” said senior study author Joan Brugge, who is also the Louise Foote Pfeiffer Professor of Cell Biology at Harvard Medical School.
Cells use oxygen to power the metabolic reactions necessary for life. But these reactions tend to generate ROS, unstably oxygenated molecules that are highly reactive and harmful to cells. Cancer cells, which multiply uncontrollably, generate large amounts of ROS.
The researchers found that TRPA1 allows cancer cells to tolerate elevated ROS by initiating a signaling cascade that inhibits programmed self-destruction—the typical fate of severely damaged or stressed cells. Further, TRPA1 expression is regulated by a signaling pathway that also produces antioxidant compounds that neutralize ROS. Antioxidants and TRPA1 appear to complement each other to increase tumor survival.
In mice with transplanted human breast tumors, blocking TRPA1 with drugs slowed tumor growth. Inhibition of TRPA1 also increased the sensitivity of cancer cells to chemotherapies that kill tumors by encouraging programmed cell death. When given together, TRPA1 blockers and chemotherapy significantly reduced tumor size.
Drugs that target TRPA1 are being developed, with some entering clinical trials, for a variety of conditions, including asthma and pain.
TRPA1 could be an enticing target for therapies against cancer. “In lung cancer, for example, radiation is an important primary therapy that kills cancer cells by flooding them with ROS,” Brugge said. “But cancer cells expressing TRPA1 may be able to tolerate radiotherapy better.”
“Inhibiting TRPA1 activity and decreasing this buffering ability might make TRPA1-positive tumors more vulnerable to radiation,” she added. “We think this could be a possible first-use scenario, if indeed good TRPA1 inhibitors are developed.”
A more detailed release from which this summary is derived can be found here.