Brain Cancer Switch
A protein controlling the growth of glioblastoma cells has been identified
NanoNewsNet based on materials from UT Southwestern Medical Center: Cellular switch controls growth of brain tumor cellsScientists from the University of Texas Southwestern Medical Center have identified a "switch" molecule, acting on which it is possible to slow down and eventually suppress the growth of the most commonly diagnosed malignant brain tumor.
The results of the work of American researchers published in the journal Cell Reports (Puliyappadamba et al., Opposing Effect of EGFRWT on EGFRvIII-Mediated NF-kB Activation with RIP1 as a Cell Death Switch), suggest that the RIP1 protein is actually an intermediary for the survival of brain tumor cells – glioblastoma multiforme – either protecting, or destroying them. Scientists believe that RIP1, present in most glioblastomas, may become a target of future drugs for the treatment of these extremely aggressive tumors.
"We have established a new mechanism involving the RIP1 protein that regulates the division and death of glioblastoma cells," comments her supervisor, associate professor of neurology and neurotherapeutics at UT Southwestern Amyn Habib, MD. "... this discovery indicates a target for the development of a possible drug treatment option, which currently does not exist".
The RIP1 protein is the main mediator of cell death in response to cellular stress, but it can also be a mediator of cell survival by activating NF-kB. RIP1 acts as an EGFR signaling switch. EGFRvIII is an oncogenic mutant that does not bind a ligand and is co-expressed with EGFRWT in glioblastoma multiforme cells. EGFRvIII binds ubiquitin ligases to RIP1, which leads to K63-mediated ubiquitination of RIP1. RIP1 binds to TAK1 and NEMO, forming the EGFRvIII-RIP1 signaling system that activates NF-kB. In glioblastoma multiforme, RIP1 plays an important role in EGFRvIII-mediated oncogenicity and correlates with NF-kB activation. Surprisingly, activation of EGFRWT by the EGF ligand leads to negative regulation of EGFRvIII with dissociation of the EGFRvIII-RIP1 signalosome, loss of ubiquitination of RIP1 and activation of NF-kB, as well as association of RIP1 with FADD and caspase-8. If EGFRWT expression exceeds EGFRvIII expression, EGF addition causes RIP1 kinase-mediated cell death. The EGFRWT-EGFRvIII-RIP1 relationship may regulate oncogenicity and sensitivity to targeted treatment of glioblastoma multiforme. (Fig. Cell Reports)To study the interrelationships of oncogenic mutant cell receptors EGFRvIII and RIP1 protein, scientists used animal models.
Both proteins are involved in the activation of NFkB, a family of proteins that mediate the growth of malignant cells. Inhibition of RIP1 in animals with an experimental model of glioblastoma leads to suppression of NFkB and signaling that stimulates tumor growth. But RIP1 can also be activated, rather than directing cancer cells along the path of self–destruction - to apoptosis and necrosis.
According to the American Cancer Society, about 30 percent of brain tumors are gliomas, a fast–growing treatment-resistant type of tumor that includes glioblastomas, astrocytomas, oligodendrogliomas and ependymomas. In many cases, the survival of patients is associated with new treatments, the development of which is at the stage of clinical trials.
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