Cells come and go throughout our lifetime. Some live a long time (like brain cells), while others constantly grow, divide and die. Cell death is a process that must be carefully managed – too many cells dying in the brain leads to neurodegenerative diseases like Alzheimer’s, while not enough cell death allows tumors to form. But not all cell death is the same. Apoptosis, often called “programmed cell death”, is neat and clean – seppuku-style cell suicide. Necrosis, on the other hand, is the messy, unplanned version of cell death – the kind that might cause pain and swelling.
Apoptosis begins by activating enzymes known as caspases, setting the cell on the path towards death – a good thing if they are cancer cells or cells infected with a virus. One caspase, known as caspase-8, is a double agent of apoptosis – depending on the conditions, it can promote either cell death or cell survival. What makes caspases-8 choose a side? A new study led by Dr. Douglas Green at St. Jude Children’s Research Hospital and Sanford-Burnham’s Dr. Guy Salvesen points the finger at a protein called FLIPL. Their study was published online March 2 in the journal Nature.
“We’ve known for some time that caspase-8 can play this dual role, but we didn’t know the molecular basis for the opposing functions. Knowing the mechanism may allow us to design therapies to defeat a cancer cell’s quest for immortality,” says Dr. Salvesen, director of the Apoptosis and Cell Death Research Program and dean of the Graduate School of Biomedical Sciences at Sanford-Burnham.
The study showed that FLIPL forms a partnership with caspase-8 and together they prevent another enzyme, RIPK3, from triggering either type of cell death. Without caspase-8, mice don’t survive. But mice bred to lack both caspase-8 and RIPK3 not only lived, but appeared fairly normal. This means that caspase-8’s inhibition of RIPK3 is absolutely required for development. But if RIPK3 is also missing, caspase-8 is no longer necessary for survival. However, as shown in this study, these double mutant mice began accumulating white blood cells later in life, a condition that resembles lymphoma. These seemingly paradoxical results are a testament to caspase-8’s dual nature in sometimes preventing cell death (allowing for growth and development) and sometimes promoting it (preventing tumor development).
What does this cascade of cellular events tell us about cancer? In a statement released by St. Jude, Dr. Green said the findings provide insight into the mechanisms at work in neuroblastoma and other tumors that suffer a loss of caspase-8. “We are beginning collaborative experiments to examine these tumors to see if RIPK3 is deleted or blocked.”
Neuroblastoma, a cancer that arises from nerve cells, is the most common solid tumor in children.
Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, Hakem R, Salvesen GS, & Green DR (2011). Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature PMID: 21368763