Manipulating the Ubiquitination Process May Overcome Glioblastoma Resistance

A complex molecular pathway protects glioblastoma, an aggressive and lethal brain cancer, from treatment based on drugs that target the TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL) apoptotic pathway.

The TRAIL apoptotic pathway has emerged as a therapeutic target for the treatment of cancer. However, clinical trials have proven that the vast majority of human cancers are resistant to this approach. In a study seeking ways to overcome this resistance, investigators at Emory University (Philadelphia, PA, USA) worked with tumor-initiating cells isolated from glioblastomas surgically removed from patients.

They reported in the January 24, 2012 online edition of the journal Cancer Discovery that A20 E3 (tumor necrosis factor, alpha-induced protein 3 or TNFAIP3) ligase was highly expressed in these cells along with receptor interacting protein 1 (RIP1), and the apoptotic protein caspase-8. Together, these proteins formed a potent signaling complex.

When TRAIL interacted with this complex, the A20 E3 ligase triggered ubiquitination and destruction of RIP1, which interfered with activation of caspase-8 and prevented caspase-8-initiated apoptosis.

These results identify A20 E3 ligase as a therapeutic target whose inhibition can overcome TRAIL resistance in glioblastoma. “Scientists in this field have been hoping to treat this cancer with this new type of apoptosis pathway-targeted therapeutic drug, and this new information may provide a path forward,” said senior author Dr. Chunhai Hao, professor of neuropathology at Emory University.

“Previous research in this area has been unable to overcome the obstacle created by resistance,” said Dr. Hao. “This research shows one of the mechanisms for how we can manipulate the ubiquitination process to overcome the resistance to the apoptosis-targeted cancer therapies. Understanding the mechanisms of resistance is vital to developing therapies going forward.”

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