Ironing Out Cancer

After more than a decade of research, scientists have discovered the natural mechanism behind a novel form of cell death called ferroptosis. The work, described in the current issue of Cell, solves a longstanding puzzle in cell biology, and points toward an entirely new strategy for treating many types of cancer and neurodegenerative diseases.  

Ferroptosis is an iron-dependent form of cell, mechanistically different from better-known cell death mechanisms such as apoptosis and necrosis. While ferroptosis has long been considered a potential tool for tumor suppression, translating that promise has been challenging. “The problem is almost every [experiment] needs chemical induction,” says Wei Gu, PhD senior author on the new paper and a member of the Cancer Genomics and Epigenomics program at the Herbert Irving Comprehensive Cancer Center. The chemicals used to induce ferroptosis in the lab are not suitable drugs by themselves, and inactivating one of the proteins involved in the chemically-induced pathway, GPX4, is lethal in animals, suggesting that any drugs targeting that pathway could be toxic. That left the field at an impasse.  

In 2015, Gu’s team discovered that a natural tumor-suppressor gene called p53 is a crucial component of the ferroptosis induction pathway, but they did not yet know what other molecules were involved. “When we published that paper, we said ‘we have to identify the native signal,’ then finally, after 10 years, we’ve identified that pathway,” says Gu.  

One reason the project took so long was the absence of leads. “The literature is dominated by this canonical [chemically-induced] pathway, so we didn’t even know where to start,” says Gu. He and his colleagues at Columbia and several other institutions decided to cast a broad net. First, they used the CRISPR-Cas9 gene editing system to inactivate each gene in the genomes of cultured cancer cells, then looked for cells that had lost the ability to induce ferroptosis in response to reactive oxygen species (ROS), a common feature of actively growing tumors. That screen identified a gene called GPX1 as a critical component of naturally-induced ferroptosis. The investigators then worked outward from GPX1, identifying other components of the natural ferroptosis pathway.  

What eventually emerged was a coordinated system of proteins and lipids that sense and respond to high levels of ROS in the cell. Because these reactive molecules cause ongoing damage to cellular systems, cells must either mitigate the damage or, in extreme cases, eliminate themselves to avoid endangering the organism. Ferroptosis is how they accomplish the latter, initiating a programmed breakdown that destroys the cell. Cancer cells typically inhibit such pathways, but the new work identifies promising ways to induce ferroptosis on demand to treat disease. 

While GPX4 is essential for cell survival, GPX1 is dispensable, unless the cell contains high levels of ROS. Animals with their GPX1 genes inactivated develop normally, providing model systems for further studies on ferroptosis. That also suggests that targeting GPX1 with drugs could provide a new treatment strategy for several diseases, including cancer. “Cancer cell proliferation is so high, they generate really high ROS levels compared to normal cells,” says Gu. “Normal tissues can tolerate the loss of GPX1, but cancer cells absolutely depend on GPX1 for survival.” High ROS levels are also hallmarks of neurodegenerative conditions such as Huntington’s disease and Parkinson’s disease.  

“We’re excited about the potential of targeting GPX1 as a new therapeutic strategy for cancer and other diseases,” says Zhangchuan Xia, PhD, the study’s first author and a postdoctoral researcher in the Gu lab. 

“We are actually in the process of making GPX1 inhibitors right now,” adds Gu. “Since it has no effect on normal cells and only affects cancer cells or other pathological cells, they may ultimately have [fewer] side effects than current therapies.”