Programmed cell death. We can’t live without it. Known as apoptosis, this natural ongoing process allows the body to get rid of unneeded or abnormal cells and enables the developing embryo to sculpt new tissues and organs.
Cancer cells elude apoptosis, giving them more time to accumulate mutations and increase invasiveness, unleashing out-of-control cell division and tumor growth.
About ten years ago, scientists discovered another type of cell death called ferroptosis. Perhaps not surprisingly, cancer cells can evade this control of
proliferation as well.
James Olzmann, associate professor of molecular biology and cell biology and nutritional sciences and toxicology, studies cancer’s ability to shield itself against ferroptosis. His Bakar Fellows Program Spark Award supports his research to strip cancer of this defense.
Q: What is the difference between the two routes of cell death — apoptosis and ferroptosis?
A: Apoptosis involves protein cleavage – enzymes called caspases cutting
hundreds of proteins. Very recent research has shown that ferroptosis is an entirely separate process involving the destruction of lipids, the fat-like
molecules that make up cell membranes and support organelles in the cell.
What led you to your research on ferroptosis specifically?
We have focused for a number of years on how cells maintain and control lipids in a steady state – the process of homeostasis. The discovery of ferroptosis provided a unique way to explore what happens when damaged lipids accumulate in cells. We started characterizing factors that are involved in either the promotion of ferroptosis or resisting this type of cell death.
No gene or protein was known to enable either ferroptosis or cancer’s ability to defend against it?
Research up to that time focused on an enzyme called GPX4 that was thought to
be absolutely essential for ferroptosis suppression. But we recognized that in
some cancers you could inhibit this enzyme and cells were still fine. You delete the enzyme and the cells continue to grow. That suggested that there must be
other ways that cancer cells can prevent ferroptosis from happening, not just GPX4.
You went searching for a different gene involved in the process?
Yes, with the advent of CRISPR technology it’s now possible to very rapidly screen genome-wide libraries. We used CRISPR to screen for genes that enable cancer cells to protect themselves from ferroptosis. We knocked out each gene independently – there are about 20,000 genes – and we asked if any of these genes were disabled, would it make cancer cell lines vulnerable to ferroptosis.
We discovered a new gene that enables cancer escape from ferroptosis. The gene encodes a protein that we named ferroptosis suppressor protein 1 (FSP1). Our paper was published alongside a paper by a group in Germany that independently discovered FSP1.
That is quite a discovery. The protein would be a prime target for a drug to pull down cancer’s shield against this form of cell death.
It was a really exciting time in the lab. We had found this protein and found that if we deleted it, it resulted in this remarkable sensitization to ferroptosis.
We sit at this interesting intersection of basic research on the one hand and also looking for therapeutic translation, which of course is what the Bakar program’s Spark Award aims to do.
What does the basic research side tell you about how FSP1 makes cancer cells resistant to ferroptosis?
The enzyme generates the antioxidant form of coenzyme COQ10 – the same enzyme in antioxidant supplements. We found that it acts on a local pool of the antioxidant and recycles it to protect the membrane from oxidation. It’s very cool. It’s a local recycling system of antioxidants.
And on the therapeutic side of the intersection?
We knew that when we deleted FSP1, we sensitized cancer to this kind of cell death. We wanted to find a small molecule – a potential drug – to inhibit FSP1. We made an in vitro assay and collaborated with Berkeley’s Drug Discovery Center. Together, we identified an FSP1 inhibitor, so instead of genetic methods
– knocking out or deleting the FSP1 gene – we can use this small molecule to inhibit the enzyme.
That is the point we are at. We have characterized these inhibitors. We’ve shown they are able to sensitize and in some cases trigger ferroptosis in cells in vitro. The Bakar Fellows program supports several key lines of experimentation. For example, it will allow us to assess the small molecule’s efficacy in combination with other drugs. It will be important to test the efficacy using preclinical mouse models of cancer.
We’ve filed a provisional patent describing our invention. I think the Spark program will give us a good chance to interact with the UC Berkeley inventor community. It will help bring the discoveries to market.