What is the role of ferroptosis in cancer?

Our cells can die in many ways, one of which is ferroptosis. Recent studies reveal that ferroptosis plays a significant role in tumor suppression, giving us new opportunities for cancer treatment.

We spoke with Boyi Gan, Ph.D., professor of  Experimental Radiation Oncology, to learn more about ferroptosis and how it is being used to advance cancer treatment.

What is ferroptosis?

Ferroptosis is a form of regulated cell death caused by a toxic buildup of lipid peroxides on cell membranes. This type of cell death requires iron, which is why it has the name “FERroptosis.” It is different from other forms of cell death, such as apoptosis. Lipid peroxides, which are generated through normal metabolic activities, can lead to oxidative damage to cell membranes.  

Our cells have powerful defense mechanisms to maintain cell survival. However, when our defense mechanisms become defective, unchecked lipid peroxides accumulate to toxic levels, damage membrane integrity and kill cells through ferroptosis.

How is ferroptosis used in cancer treatment?

Scientists have designed and identified various compounds called ferroptosis inducers. They are capable of disabling ferroptosis defense systems and triggering cells to undergo ferroptosis. Some ferroptosis inducers have been shown to provoke potent ferroptosis in cancer cells. In certain animal models, this caused suppression in tumor growth.

Cancer therapies like immunotherapy, chemotherapy and radiation therapy also can induce ferroptosis in cancer cells.  

A study that I led with a team of MD Anderson researchers and published in Cell Research shows ionizing radiation induces ferroptosis in cancer cells. Radiation therapy uses high-energy ionizing radiation to generate reactive oxygen species. This attacks lipid molecules in cells to produce lipid peroxides and create ferroptosis.  

Another study published in Nature shows immunotherapy-activated cytotoxic T cells release a cytokine molecule called interferon-gamma. Interferon-gamma can promote tumor cell ferroptosis by weakening the defense in tumor cells. 

These studies inspire interest in combining ferroptosis inducers with the standard of care treatment options like chemotherapy and radiation therapy. Our goal is to bring better results and make cancer treatment as effective as possible.

Why are you and other researchers studying this type of cell death in cancer therapy? 

Most cancer treatments, such as immunotherapy, chemotherapy and radiation therapy, are designed to kill cancer cells primarily by inducing a type of cell death called apoptosis. Over time, though, many cancer cells figure out a way to evade apoptosis. When this happens, tumors develop resistance to drug therapy and other forms of cancer treatment. This can lead to disease recurrence. 

Because apoptosis and ferroptosis involve different molecular machineries, ferroptosis-inducing therapies might provide an effective approach to overcoming therapy resistance in cancers that do not respond to treatment. 

This is why it is critical to have a deeper understanding of ferroptosis in cancer, so we can design therapies to better target this type of cell death in cancer treatment.

What is next for ferroptosis research? 

Targeting ferroptosis may be a viable strategy to treat cancer. But many of the mechanisms regulating ferroptosis are still unknown. By learning more about how ferroptosis is regulated, we hope to be able to identify additional targets for developing new ferroptosis-inducing cancer therapies. We also need to develop more potent ferroptosis inducers that can be used for treating patients.  

Because ferroptosis can occur in both cancer cells and normal cells, it remains a challenge to selectively induce ferroptosis in tumors while protecting normal tissues.

Here at MD Anderson, our study of ferroptosis continues to improve how we can use it in cancer treatment so that we will, hopefully, one day, achieve our goal to end cancer. 

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