Interacting Signaling Networks Modulate Brain Tumor Aggressiveness

A recent paper reported that high levels of receptor interacting protein 1 (RIP1), a central component of the NF-kappaB signaling network, were present in patients with the most aggressive and lethal form of the malignant brain tumor glioblastoma.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) were interested in establishing a connection between two important signaling networks. The network linked to nuclear factor-kappaB (NF-kappaB) activation is thought to play an important role in the pathogenesis of cancer and also in resistance to treatment. The other network, focused on the inactivation of the p53 tumor suppressor, is known to be a key component in the development of most cancers.

In their paper published in the April 2009 issue of the journal Cancer Research the investigators showed that RIP1 negatively regulated p53 tumor suppressor signaling. Loss of RIP1 from cells resulted in increased induction of p53 in response to DNA damage, whereas higher RIP1 levels lead to a complete shutdown of DNA damage-induced p53 induction. As part of the study the investigators analyzed tumor tissues from 92 patients to determine the distribution of RIP1 in each. They found a direct correlation between the aggressiveness of the tumor and the level of RIP1.

"This is the first report of high RIP1 levels being associated with any type of cancer," said senior author Dr. Amyn Habib, assistant professor of neurology at the University of Texas Southwestern Medical Center. "RIP1 activates NF-kappaB and then that increases the expression of a gene called mdm2, which inhibits the p53 gene. Inhibition of p53 allows cells with damaged DNA to proliferate and potentially to become cancerous. Our data suggests that increased expression of RIP1 could serve as a marker to identify patients who have a significantly worse prognosis and who will likely be resistant to chemotherapy."

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University of Texas Southwestern Medical Center