LA JOLLA, Calif., July 24, 2009 Scientists at Burnham Institute for Medical Research (Burnham) have found that the Caspase-8 protein, long known to play a major role in promoting programmed cell death (apoptosis), helps relay signals that can cause cancer cells to proliferate, migrate and invade surrounding tissues. The study was published in the journal Cancer Research on June 15.
The team of scientists, led by Kristiina Vuori, M.D., Ph.D., professor and director of the Cancer Center at Burnham, showed that Caspase-8 caused neuroblastoma cancer cells to proliferate and migrate. For the first time, Caspase-8 was shown to play a key role in relaying the growth signals from epidermal growth factor (EGF) that cause cell division and invasion. The researchers also identified an RXDLL amino acid motif that controls the signaling from the EGF receptor through the protein kinase Src to the master cell proliferation regulator protein, MAPK. This same signaling pathway stimulates neuroblastoma cells to migrate and invade neighboring tissues--a critical process in cancer metastasis.
"Caspase-8 has a well defined role in promoting apoptosis, especially in response to activation of the so-called death receptors on the outside of cells," said Darren Finlay, Ph.D., first author on the paper. "Although Caspase-8 is involved in apoptosis, it is rarely deleted or silenced in tumors, suggesting that it was giving cancer cells a leg up in some other way. Our studies suggest that Caspase-8 does so by activating the MAPK pathway through Src."
Using immuno-blot assays, the scientists showed that EGF signaling was absent in a cancer cell line that is deficient in Caspase-8 and that EGF signaling can be restored by reconstituting the cells with wildtype Caspase-8. Sequence homology studies helped to identify a RXDLL motif in the protein, a sequence that has been shown in other proteins to function in cell signaling. The researchers also used immun
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