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Scientists at Montana State University have discovered a previously unknown cellular pathway that allows mammalian cells to produce the essential amino acid cysteine even when the molecular systems normally responsible for making it available have stopped functioning.
The discovery challenges a long-standing assumption about how cells survive and could eventually help researchers develop strategies for making some cancer cells more vulnerable to treatment. The findings were published in Nature Chemical Biology.
Cysteine is essential for life. Cells use it to build proteins, protect themselves against cellular damage and form disulfide bonds that help maintain the structure of proteins. Because cysteine is not readily available outside cells, mammalian cells normally obtain it by converting cystine, its oxidized form, through a system known as disulfide reductase.
Scientists had long believed that at least one functioning disulfide reductase was necessary for cells to survive.
Ed Schmidt, a professor of genetics and development at Montana State University, began questioning that assumption after experiments with genetically engineered mice produced an unexpected result. In 2014, a colony of mice survived despite lacking the known mechanisms required to convert cystine into cysteine.
Schmidt had previously created mice whose liver cells lacked one of two major disulfide reductases. When the animals displayed unexpected physiological responses, he decided to investigate whether cells could survive without either system.
The research eventually revealed a hidden backup pathway. Working with Peter Nagy and researchers at the Hungarian National Institute of Oncology, Schmidt’s team found that cells can break a carbon-sulfur bond within cystine through an alternative chemical reaction. This releases cysteine without relying on the conventional disulfide reductase systems.
The researchers believe the pathway may have evolved as an ancient defense against electrophilic toxins, chemical compounds that can damage cells and are produced by various organisms. The mechanism may have helped early multicellular organisms withstand toxic substances encountered in their environment.
The discovery could also have implications for cancer treatment. Schmidt’s team suspects that cancer cells may use the same pathway to withstand the cellular stress caused by chemotherapy, radiation and immune-based treatments. If researchers can selectively block the pathway in tumors, they may be able to make cancer cells more susceptible to existing therapies.
Several Montana State students contributed to the nine-year project, including undergraduate researchers Zoe Seaford and Sydney Austad, who were co-first authors. Other students and researchers from multiple institutions also participated in the work.
The researchers now face the task of determining how widespread the pathway is and whether it can be safely targeted in cancer cells without harming healthy tissue.
