Biologists have long held that a cell cannot live without at least one working disulfide reductase system, the machinery that turns cystine into the amino acid cysteine. A Montana State University team has now shown that mammalian cells have a backup route, and that cancer cells may lean on it to survive treatment.
The work, published in Nature Chemical Biology, was led by Ed Schmidt, a professor of genetics and development in the university’s Department of Microbiology and Cell Biology. “All cells need a constant supply of an amino acid called cysteine in order to stay alive,” he said, “yet cysteine is not available outside of the cells.” Cysteine builds proteins, helps cells guard against damage and forms the disulfide bonds that hold proteins in shape. Cells get it by breaking apart cystine, an oxidized form of the molecule.
Mice that should not have lived
The first clue came in 2014, when a colony of genetically engineered mice survived under conditions that were supposed to be fatal. The animals had no known way to convert cystine into cysteine. “This was supposed to be impossible,” Schmidt said. It was not a chance sighting. He had earlier engineered mice whose liver cells each lacked one of the two main disulfide reductases, and their responses made him doubt the standard assumption. “I wanted to test this,” he said.
Explaining the survival took another seven years, with analytical help from Peter Nagy and his group at the Hungarian National Institute of Oncology in Budapest. The team found that when the usual pathway is out of action, cells break an adjacent carbon-sulfur bond in cystine, which frees cysteine for use.
Why it matters for cancer
Schmidt suggests the backup evolved in early multicellular ancestors as a defense against electrophilic toxins, chemical weapons made by predators or rivals. The catch is that the same shield may protect tumors. Researchers suspect some cancer cells use it to withstand chemotherapy, radiation and immune therapy. “Now that we know they have this defense mechanism, we might be able to precisely disable it in cancers,” Schmidt said, which could make them more susceptible to treatment. Nobody has yet shown how to block the pathway in tumors alone, and that is the next job.
Undergraduates Zoe Seaford and Sydney Austad were co-first authors. Martina Serrano Alvarez and Reed Noyd also took part as undergraduates, and doctoral student Colin Miller contributed. “This scientific breakthrough underscores the power of research to redefine what we thought was possible,” said Sreekala Bajwa, dean of the agricultural college.
