Scientists have identified the mechanism by which compounds of arsenic can actually have therapeutic properties when used to treat certain types of cancer.
Therapeutic use of the poison arsenic to treat acute promyelocytic leukaemia leads to modification of the oncoprotein PML-RARalpha, causing its degradation. Two studies published online in Nature Cell Biology identify an enzyme that modifies proteins for destruction, known as ubiquitin ligase RNF4, as being responsible for recognizing PML-RARalpha and targeting it for degradation.
Originally identified in 1992 as the active ingredient in a traditional Chinese medicine, arsenic trioxide (ATO) has since been used to treat acute promyelocytic leukemia -- a cancer of the blood and bone marrow. However, the mechanism of ATO action had remained unknown. Previous studies have shown that ATO treatment causes modification of PML-RARalpha by addition of several copies of the signalling molecule SUMO. How this modification correlates with the observed loss of PML-RARalpha was unclear.
Two studies from Ronald T. Hay and Hugues de The show that RNF4 specifically recognizes the SUMO chains attached to PML-RARalpha. RNF4 can then add further ubiquitin modifications to target the oncoprotein for degradation by the proteasome. Interestingly, PML-RARalpha represents the first cellular substrate of RNF4 to be identified.
This work adds vital information into how arsenic and arsenic-related compounds can be used as therapeutic agents to treat haematological cancers and could aid the development of improved treatments.
Ronald T. Hay (University of Dundee, UK)
Hugues de The (CNRS/Universite de Paris, France)
Abstracts available online:
Abstract of Paper 1.
Abstract of Paper 2.
(C) Nature Cell Biology press release.
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