Restoring the Antizyme Tumor Suppressor

Antizyme is a protein that regulates cell growth by promoting degradation of certain growth-promoting molecules in normal cells.

Antizyme is itself regulated by a naturally occurring inhibitor called Antizyme Inhibitor (AZIN)

Excess AZIN in tumor cells causes excess tumor cell growth by suppressing antizyme activity

Recent advances in our understanding of antizyme and AZIN have demonstrated that:

1.      AZIN works by binding to antizyme. When bound to AZIN, antizyme can no longer function as a tumor supressor.

2.      Certain cancer cells make a more potent version of AZIN that makes cancer cells grow faster and move faster.

3.     The more potent form of AZIN arises by natural gene editing in which a single amino acid is changed

Questions being pursued in our laboratory:

• Can we prevent binding of AZIN to antizyme and restore tumor suppression?  We propose that a drug that would prevent AZIN binding to antizyme would allow antizyme to function better as a tumor suppressor.  Working with Dr. Michael Rogers at Boston Children's Hospital, we are currently screening drug libraries to detect molecules that block AZIN-antizyme binding. We believe that such drugs could provide a new means of suppressing cancer cell growth in patients.      

• Can we understand how a single amino acid substitution in AZIN leads to increased tumor promoting activity.  Work in our lab is leading to a new understanding of the structural changes that lead to these effects.  This understanding could unlock new approaches to dampen the tumor promoting activity of the edited form of AZIN.

• For further reading, see: Olsen R and Zetter BR: Evidence of a role for antizyme and antizyme inhibitor as regulators of human cancer. Mol Cancer Res 2011, 9:1285-1293 or Ghalali A, Rice JM, Kusztos A, Jernigan F, Zetter BR, Rogers MS. Developing a novel FRET assay, targeting the binding between Antizyme-AZIN. Sci Rep 2019; 9:4632.